Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Identifieur interne : 005059 ( Istex/Corpus ); précédent : 005058; suivant : 005060Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding
Auteurs : Brent A. Appleton ; Ping Wu ; Janice Maloney ; Jianping Yin ; Wei-Ching Liang ; Scott Stawicki ; Kyle Mortara ; Krista K. Bowman ; J Michael Elliott ; William Desmarais ; J Fernando Bazan ; Anil Bagri ; Marc Tessier-Lavigne ; Alexander W. Koch ; Yan Wu ; Ryan J. Watts ; Christian WiesmannSource :
- The EMBO Journal [ 0261-4189 ] ; 2007-11-28.
Abstract
Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.
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DOI: 10.1038/sj.emboj.7601906
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Appleton</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Wu, Ping" sort="Wu, Ping" uniqKey="Wu P" first="Ping" last="Wu">Ping Wu</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Maloney, Janice" sort="Maloney, Janice" uniqKey="Maloney J" first="Janice" last="Maloney">Janice Maloney</name><affiliation><mods:affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Yin, Jianping" sort="Yin, Jianping" uniqKey="Yin J" first="Jianping" last="Yin">Jianping Yin</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Liang, Wei Hing" sort="Liang, Wei Hing" uniqKey="Liang W" first="Wei-Ching" last="Liang">Wei-Ching Liang</name><affiliation><mods:affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Stawicki, Scott" sort="Stawicki, Scott" uniqKey="Stawicki S" first="Scott" last="Stawicki">Scott Stawicki</name><affiliation><mods:affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Mortara, Kyle" sort="Mortara, Kyle" uniqKey="Mortara K" first="Kyle" last="Mortara">Kyle Mortara</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Bowman, Krista K" sort="Bowman, Krista K" uniqKey="Bowman K" first="Krista K" last="Bowman">Krista K. Bowman</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Elliott, J Michael" sort="Elliott, J Michael" uniqKey="Elliott J" first="J Michael" last="Elliott">J Michael Elliott</name><affiliation><mods:affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Desmarais, William" sort="Desmarais, William" uniqKey="Desmarais W" first="William" last="Desmarais">William Desmarais</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Bazan, J Fernando" sort="Bazan, J Fernando" uniqKey="Bazan J" first="J Fernando" last="Bazan">J Fernando Bazan</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Bagri, Anil" sort="Bagri, Anil" uniqKey="Bagri A" first="Anil" last="Bagri">Anil Bagri</name><affiliation><mods:affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Tessier Avigne, Marc" sort="Tessier Avigne, Marc" uniqKey="Tessier Avigne M" first="Marc" last="Tessier-Lavigne">Marc Tessier-Lavigne</name><affiliation><mods:affiliation>Department of Research Drug Discovery, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Koch, Alexander W" sort="Koch, Alexander W" uniqKey="Koch A" first="Alexander W" last="Koch">Alexander W. Koch</name><affiliation><mods:affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><affiliation><mods:affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Watts, Ryan J" sort="Watts, Ryan J" uniqKey="Watts R" first="Ryan J" last="Watts">Ryan J. Watts</name><affiliation><mods:affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation></author><author><name sortKey="Wiesmann, Christian" sort="Wiesmann, Christian" uniqKey="Wiesmann C" first="Christian" last="Wiesmann">Christian Wiesmann</name><affiliation><mods:affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: chw@gene.com</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The EMBO Journal</title><title level="j" type="alt">THE EMBO JOURNAL</title><idno type="ISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><imprint><biblScope unit="vol">26</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="4902">4902</biblScope><biblScope unit="page" to="4912">4912</biblScope><biblScope unit="page-count">11</biblScope><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2007-11-28">2007-11-28</date></imprint><idno type="ISSN">0261-4189</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0261-4189</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>nrp1</json:string><json:string>nrp2</json:string><json:string>vegf</json:string><json:string>receptor</json:string><json:string>nrps</json:string><json:string>sema3a</json:string><json:string>semaphorins</json:string><json:string>biol</json:string><json:string>supplementary figure</json:string><json:string>vander kooi</json:string><json:string>kooi</json:string><json:string>vander</json:string><json:string>crystal structures</json:string><json:string>embo</json:string><json:string>neuropilin</json:string><json:string>semaphorin</json:string><json:string>embo journal</json:string><json:string>dimer</json:string><json:string>biol chem</json:string><json:string>liang</json:string><json:string>chem</json:string><json:string>growth factor</json:string><json:string>crystal 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binding</json:string><json:string>extracellular domains</json:string><json:string>proc natl acad</json:string><json:string>crystal forms</json:string><json:string>molecular surface</json:string><json:string>sema3 binding</json:string><json:string>molecular replacement</json:string><json:string>acta crystallogr</json:string><json:string>electron density</json:string><json:string>biol crystallogr</json:string><json:string>growth cones</json:string><json:string>vascular</json:string><json:string>chen</json:string></teeft></keywords><author><json:item><name>Brent A Appleton</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Ping Wu</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Janice Maloney</name><affiliations><json:string>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>JianPing Yin</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Wei‐Ching Liang</name><affiliations><json:string>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Scott Stawicki</name><affiliations><json:string>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Kyle Mortara</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Krista K Bowman</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>J Michael Elliott</name><affiliations><json:string>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>William Desmarais</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>J Fernando Bazan</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Anil Bagri</name><affiliations><json:string>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Marc Tessier‐Lavigne</name><affiliations><json:string>Department of Research Drug Discovery, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Alexander W Koch</name><affiliations><json:string>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Yan Wu</name><affiliations><json:string>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Ryan J Watts</name><affiliations><json:string>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</json:string></affiliations></json:item><json:item><name>Christian Wiesmann</name><affiliations><json:string>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</json:string><json:string>E-mail: chw@gene.com</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>neuropilin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neuroscience</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tumorigenesis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>vasculogenesis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>X‐ray crystallography</value></json:item></subject><articleId><json:string>EMBJ7601906</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</abstract><qualityIndicators><score>6.86</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595 x 794 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1019</abstractCharCount><pdfWordCount>7995</pdfWordCount><pdfCharCount>48472</pdfCharCount><pdfPageCount>11</pdfPageCount><abstractWordCount>155</abstractWordCount></qualityIndicators><title>Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</title><genre><json:string>article</json:string></genre><host><title>The EMBO 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& Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><availability><licence>Copyright © 2007 European Molecular Biology Organization</licence></availability><date type="published" when="2007-11-28"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</title><title level="a" type="short">Crystal structures of Nrp/Fab complexes</title><author xml:id="author-0000"><persName><forename type="first">Brent A</forename><surname>Appleton</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Ping</forename><surname>Wu</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">Janice</forename><surname>Maloney</surname></persName><affiliation><orgName>Department of Tumor Biology & Angiogenesis, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">JianPing</forename><surname>Yin</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0004"><persName><forename type="first">Wei‐Ching</forename><surname>Liang</surname></persName><affiliation><orgName>Department of Antibody Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0005"><persName><forename type="first">Scott</forename><surname>Stawicki</surname></persName><affiliation><orgName>Department of Antibody Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0006"><persName><forename type="first">Kyle</forename><surname>Mortara</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0007"><persName><forename type="first">Krista K</forename><surname>Bowman</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0008"><persName><forename type="first">J Michael</forename><surname>Elliott</surname></persName><affiliation><orgName>Department of Protein Chemistry, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0009"><persName><forename type="first">William</forename><surname>Desmarais</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation><note type="foot"></note></author><author xml:id="author-0010"><persName><forename type="first">J Fernando</forename><surname>Bazan</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0011"><persName><forename type="first">Anil</forename><surname>Bagri</surname></persName><affiliation><orgName>Department of Tumor Biology & Angiogenesis, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0012"><persName><forename type="first">Marc</forename><surname>Tessier‐Lavigne</surname></persName><affiliation><orgName>Department of Research Drug Discovery, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0013"><persName><forename type="first">Alexander W</forename><surname>Koch</surname></persName><affiliation><orgName>Department of Protein Chemistry, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0014"><persName><forename type="first">Yan</forename><surname>Wu</surname></persName><affiliation><orgName>Department of Antibody Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0015"><persName><forename type="first">Ryan J</forename><surname>Watts</surname></persName><affiliation><orgName>Department of Tumor Biology & Angiogenesis, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation></author><author xml:id="author-0016" role="corresp"><persName><forename type="first">Christian</forename><surname>Wiesmann</surname></persName><affiliation><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><settlement type="city">South San Francisco</settlement><region>CA</region><country key="US">USA</country></address></affiliation><affiliation>Corresponding author. Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 7484; Fax: +1 650 225 3734; E-mail: chw@gene.com</affiliation></author><idno type="istex">AB5729DC76EAF891407A74B81AF7C8627DDA7FFB</idno><idno type="DOI">10.1038/sj.emboj.7601906</idno><idno type="unit">EMBJ7601906</idno><idno type="toTypesetVersion">file:EMBJ.EMBJ7601906.pdf</idno></analytic><monogr><title level="j" type="main">The EMBO Journal</title><title level="j" type="alt">THE EMBO JOURNAL</title><idno type="pISSN">0261-4189</idno><idno type="eISSN">1460-2075</idno><idno type="book-DOI">10.1002/(ISSN)1460-2075</idno><idno type="book-part-DOI">10.1002/emboj.v26.23</idno><idno type="product">EMBJ</idno><imprint><biblScope unit="vol">26</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="4902">4902</biblScope><biblScope unit="page" to="4912">4912</biblScope><biblScope unit="page-count">11</biblScope><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2007-11-28"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract style="main"><p>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with <hi rend="italic">in vitro</hi> experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</p></abstract><textClass><keywords><term xml:id="embj7601906-kwd-0001">neuropilin</term><term xml:id="embj7601906-kwd-0002">neuroscience</term><term xml:id="embj7601906-kwd-0003">tumorigenesis</term><term xml:id="embj7601906-kwd-0004">vasculogenesis</term><term xml:id="embj7601906-kwd-0005">X‐ray crystallography</term></keywords><classCode scheme="http://psi.embo.org/14602075/EMBO37">Signal Transduction</classCode><classCode scheme="http://psi.embo.org/14602075/EMBO40">Structural Biology</classCode><classCode scheme="articleCategory">Article</classCode><classCode scheme="tocHeading1">Article</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/AB5729DC76EAF891407A74B81AF7C8627DDA7FFB/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component type="serialArticle" version="2.0" xml:lang="en" xml:id="embj7601906"><header><publicationMeta level="product"><publisherInfo><publisherName>John Wiley & Sons, Ltd</publisherName><publisherLoc>Chichester, UK</publisherLoc></publisherInfo><doi>10.1002/(ISSN)1460-2075</doi><issn type="print">0261-4189</issn><issn type="electronic">1460-2075</issn><idGroup><id type="product" value="EMBJ"></id></idGroup><titleGroup><title type="main" sort="THE EMBO JOURNAL">The EMBO Journal</title></titleGroup></publicationMeta><publicationMeta level="part" position="230"><doi>10.1002/emboj.v26.23</doi><copyright ownership="publisher">Copyright © 2013 Wiley Periodicals, Inc</copyright><numberingGroup><numbering type="journalVolume" number="26">26</numbering><numbering type="journalIssue">23</numbering></numberingGroup><coverDate startDate="2007-11-28">November 28, 2007</coverDate></publicationMeta><publicationMeta level="unit" position="100" type="article" status="forIssue"><doi>10.1038/sj.emboj.7601906</doi><idGroup><id type="unit" value="EMBJ7601906"></id></idGroup><countGroup><count type="pageTotal" number="11"></count></countGroup><titleGroup>
<title type="articleCategory">Article</title><title type="tocHeading1">Article</title></titleGroup><copyright ownership="thirdParty">Copyright © 2007 European Molecular Biology Organization</copyright><eventGroup><event type="manuscriptReceived" date="2007-06-28"></event><event type="manuscriptAccepted" date="2007-10-08"></event><event type="publishedOnlineEarlyUnpaginated" date="2007-11-08"></event><event type="publishedOnlineFinalForm" date="2007-11-28"></event><event type="xmlConverted" agent="SPi Global Converter_TO_WileyML3Gv2.0 version:1.0; WileyML 3G Packaging Tool v1.0" date="2013-10-17"></event><event type="xmlCorrected" agent="Wiley-VCH" date="2013-11-19"></event><event type="firstOnline" date="2007-11-08"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">4902</numbering><numbering type="pageLast">4912</numbering></numberingGroup><correspondenceTo>Corresponding author. Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 7484; Fax: +1 650 225 3734; E-mail: <email>chw@gene.com</email></correspondenceTo><subjectInfo><subject href="http://psi.embo.org/14602075/EMBO37">Signal Transduction</subject><subject href="http://psi.embo.org/14602075/EMBO40">Structural Biology</subject></subjectInfo><attributeValueGroup><attributeValue element="note" attribute="type" value="present-address"></attributeValue></attributeValueGroup><linkGroup><link type="toTypesetVersion" href="file:EMBJ.EMBJ7601906.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</title><title type="short">Crystal structures of Nrp/Fab complexes</title></titleGroup><creators><creator creatorRole="author" xml:id="embj7601906-cr-0001" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>Brent A</givenNames><familyName>Appleton</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0002" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>Ping</givenNames><familyName>Wu</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0003" affiliationRef="#embj7601906-aff-0002"><personName><givenNames>Janice</givenNames><familyName>Maloney</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0004" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>JianPing</givenNames><familyName>Yin</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0005" affiliationRef="#embj7601906-aff-0003"><personName><givenNames>Wei‐Ching</givenNames><familyName>Liang</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0006" affiliationRef="#embj7601906-aff-0003"><personName><givenNames>Scott</givenNames><familyName>Stawicki</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0007" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>Kyle</givenNames><familyName>Mortara</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0008" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>Krista K</givenNames><familyName>Bowman</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0009" affiliationRef="#embj7601906-aff-0004"><personName><givenNames>J Michael</givenNames><familyName>Elliott</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0010" affiliationRef="#embj7601906-aff-0001" noteRef="#embj7601906-note-0001"><personName><givenNames>William</givenNames><familyName>Desmarais</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0011" affiliationRef="#embj7601906-aff-0001"><personName><givenNames>J Fernando</givenNames><familyName>Bazan</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0012" affiliationRef="#embj7601906-aff-0002"><personName><givenNames>Anil</givenNames><familyName>Bagri</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0013" affiliationRef="#embj7601906-aff-0005"><personName><givenNames>Marc</givenNames><familyName>Tessier‐Lavigne</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0014" affiliationRef="#embj7601906-aff-0004"><personName><givenNames>Alexander W</givenNames><familyName>Koch</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0015" affiliationRef="#embj7601906-aff-0003"><personName><givenNames>Yan</givenNames><familyName>Wu</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0016" affiliationRef="#embj7601906-aff-0002"><personName><givenNames>Ryan J</givenNames><familyName>Watts</familyName></personName></creator><creator creatorRole="author" xml:id="embj7601906-cr-0017" affiliationRef="#embj7601906-aff-0001" corresponding="yes"><personName><givenNames>Christian</givenNames><familyName>Wiesmann</familyName></personName></creator></creators><affiliationGroup><affiliation countryCode="US" type="organization" xml:id="embj7601906-aff-0001"><orgName>Department of Protein Engineering, Genentech, Inc.</orgName><address><city>South San Francisco</city><countryPart>CA</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="embj7601906-aff-0002"><orgName>Department of Tumor Biology & Angiogenesis, Genentech, Inc.</orgName><address><city>South San Francisco</city><countryPart>CA</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="embj7601906-aff-0003"><orgName>Department of Antibody Engineering, Genentech, Inc.</orgName><address><city>South San Francisco</city><countryPart>CA</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="embj7601906-aff-0004"><orgName>Department of Protein Chemistry, Genentech, Inc.</orgName><address><city>South San Francisco</city><countryPart>CA</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="embj7601906-aff-0005"><orgName>Department of Research Drug Discovery, Genentech, Inc.</orgName><address><city>South San Francisco</city><countryPart>CA</countryPart><country>USA</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="embj7601906-kwd-0001">neuropilin</keyword><keyword xml:id="embj7601906-kwd-0002">neuroscience</keyword><keyword xml:id="embj7601906-kwd-0003">tumorigenesis</keyword><keyword xml:id="embj7601906-kwd-0004">vasculogenesis</keyword><keyword xml:id="embj7601906-kwd-0005">X‐ray crystallography</keyword></keywordGroup><supportingInformation><supportingInfoItem xml:id="embj7601906-sup-0001"><mediaResource alt="supplementary data" mimeType="application/doc" href="urn-x:wiley:02614189:media:embj7601906:embj7601906-sup-0001"></mediaResource><caption><p>Supplementary Figure S1–S8</p></caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><p>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with <i>in vitro</i> experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="embj7601906-note-0001" type="present-address">Present address: Lilly Corporate Center, Indianapolis, IN 46285, USA</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Crystal structures of Nrp/Fab complexes</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding</title></titleInfo><name type="personal"><namePart type="given">Brent A</namePart><namePart type="family">Appleton</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ping</namePart><namePart type="family">Wu</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Janice</namePart><namePart type="family">Maloney</namePart><affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">JianPing</namePart><namePart type="family">Yin</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wei‐Ching</namePart><namePart type="family">Liang</namePart><affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Scott</namePart><namePart type="family">Stawicki</namePart><affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kyle</namePart><namePart type="family">Mortara</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Krista K</namePart><namePart type="family">Bowman</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J Michael</namePart><namePart type="family">Elliott</namePart><affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William</namePart><namePart type="family">Desmarais</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><description>Present address: Lilly Corporate Center, Indianapolis, IN 46285, USA</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J Fernando</namePart><namePart type="family">Bazan</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anil</namePart><namePart type="family">Bagri</namePart><affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marc</namePart><namePart type="family">Tessier‐Lavigne</namePart><affiliation>Department of Research Drug Discovery, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexander W</namePart><namePart type="family">Koch</namePart><affiliation>Department of Protein Chemistry, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yan</namePart><namePart type="family">Wu</namePart><affiliation>Department of Antibody Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ryan J</namePart><namePart type="family">Watts</namePart><affiliation>Department of Tumor Biology & Angiogenesis, Genentech, Inc., CA, South San Francisco, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Wiesmann</namePart><affiliation>Department of Protein Engineering, Genentech, Inc., CA, South San Francisco, USA</affiliation><affiliation>E-mail: chw@gene.com</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>John Wiley & Sons, Ltd</publisher><place><placeTerm type="text">Chichester, UK</placeTerm></place><dateIssued encoding="w3cdtf">2007-11-28</dateIssued><dateCaptured encoding="w3cdtf">2007-06-28</dateCaptured><dateValid encoding="w3cdtf">2007-10-08</dateValid><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Neuropilins (Nrps) are co‐receptors for class 3 semaphorins and vascular endothelial growth factors and important for the development of the nervous system and the vasculature. The extracellular portion of Nrp is composed of two domains that are essential for semaphorin binding (a1a2), two domains necessary for VEGF binding (b1b2), and one domain critical for receptor dimerization (c). We report several crystal structures of Nrp1 and Nrp2 fragments alone and in complex with antibodies that selectively block either semaphorin or vascular endothelial growth factor (VEGF) binding. In these structures, Nrps adopt an unexpected domain arrangement in which the a2, b1, and b2 domains form a tightly packed core that is only loosely connected to the a1 domain. The locations of the antibody epitopes together with in vitro experiments indicate that VEGF and semaphorin do not directly compete for Nrp binding. Based upon our structural and functional data, we propose possible models for ligand binding to neuropilins.</abstract><note type="additional physical form">Supplementary Figure S1–S8</note><subject><genre>keywords</genre><topic>neuropilin</topic><topic>neuroscience</topic><topic>tumorigenesis</topic><topic>vasculogenesis</topic><topic>X‐ray crystallography</topic></subject><relatedItem type="host"><titleInfo><title>The EMBO Journal</title></titleInfo><genre type="journal">journal</genre><subject><genre>index-terms</genre><topic authorityURI="http://psi.embo.org/14602075/EMBO37">Signal Transduction</topic><topic authorityURI="http://psi.embo.org/14602075/EMBO40">Structural Biology</topic></subject><subject><genre>article-category</genre><topic>Article</topic></subject><identifier type="ISSN">0261-4189</identifier><identifier type="eISSN">1460-2075</identifier><identifier type="DOI">10.1002/(ISSN)1460-2075</identifier><identifier type="PublisherID">EMBJ</identifier><part><date>2007</date><detail type="volume"><caption>vol.</caption><number>26</number></detail><detail type="issue"><caption>no.</caption><number>23</number></detail><extent unit="pages"><start>4902</start><end>4912</end><total>11</total></extent></part></relatedItem><identifier type="istex">AB5729DC76EAF891407A74B81AF7C8627DDA7FFB</identifier><identifier type="DOI">10.1038/sj.emboj.7601906</identifier><identifier type="ArticleID">EMBJ7601906</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2013 Wiley Periodicals, IncCopyright © 2007 European Molecular Biology Organization</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>John Wiley & Sons, Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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