Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex
Identifieur interne : 001789 ( Istex/Corpus ); précédent : 001788; suivant : 001790Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex
Auteurs : Chin Hsiung Lin ; Dinshaw J. PatelSource :
- Journal of Molecular Biology [ 0022-2836 ] ; 1995.
English descriptors
- KwdEn :
- Teeft :
- Adduct, Adenine, Alkylation, Amino, Amino protons, Antibiotic, Antitumor antibiotic, Binding site, Biochemistry, Boger, Central segment, Charge delocalization, Chem, Chemical shifts, Complex formation, Complex structure, Control hairpin duplex, Covalent, Covalent adducts, Covalent site, Covalently, Crosspeaks, Distance restraints, Distance structures, Drug molecule, Duocarmycin, Duocarmycin duplex, Duplex, Duplex level, Energy minimization, Exchangeable, Exchangeable protons, Exhibits noes, Experimental procedures, Groove, Hairpin, Hairpin duplex, Helix, Helix axis, Hurley, Imino, Imino proton, Imino protons, Input distance restraints, Large number, Matrix, Minor groove, Minor groove sugar, Minor groove width, Molecular dynamics, Molecular dynamics calculations, Noesy, Noesy contour plot, Noesy contour plots, Nucleic, Nucleic acid protons, Patel, Phosphorus, Phosphorus atoms, Phosphorus resonances, Proton, Proton restraints, Relaxation matrix, Relaxation matrix structures, Representative relaxation matrix structure, Right panel, Sodium phosphate, Solution structure, Stereo views, Structure calculations, Time step, Xplor program.
Abstract
Abstract: Duocarmycin A is an antitumour antibiotic that binds covalently to the minor groove N-3 position of adenine with sequence specificity for the 3′-adenine in a d(A-A-A-A) tract in duplex DNA. The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12+) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12+) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12+modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width andx-displacement parameters indicative of aB-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.
Url:
DOI: 10.1006/jmbi.1995.0209
Links to Exploration step
ISTEX:59C8080AC1AC1D4DDEE3300653A774572D8A68E0Le document en format XML
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The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12+) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12+) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12+modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width andx-displacement parameters indicative of aB-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>duocarmycin</json:string><json:string>minor groove</json:string><json:string>duplex</json:string><json:string>covalent</json:string><json:string>duocarmycin duplex</json:string><json:string>adduct</json:string><json:string>proton</json:string><json:string>imino</json:string><json:string>adenine</json:string><json:string>groove</json:string><json:string>covalently</json:string><json:string>exchangeable</json:string><json:string>hairpin duplex</json:string><json:string>noesy</json:string><json:string>alkylation</json:string><json:string>hairpin</json:string><json:string>imino proton</json:string><json:string>biochemistry</json:string><json:string>patel</json:string><json:string>matrix</json:string><json:string>solution structure</json:string><json:string>boger</json:string><json:string>helix</json:string><json:string>distance restraints</json:string><json:string>complex formation</json:string><json:string>chem</json:string><json:string>crosspeaks</json:string><json:string>drug molecule</json:string><json:string>exhibits noes</json:string><json:string>phosphorus resonances</json:string><json:string>hurley</json:string><json:string>phosphorus</json:string><json:string>sodium phosphate</json:string><json:string>experimental procedures</json:string><json:string>exchangeable protons</json:string><json:string>representative relaxation matrix structure</json:string><json:string>molecular dynamics calculations</json:string><json:string>relaxation matrix structures</json:string><json:string>antibiotic</json:string><json:string>structure calculations</json:string><json:string>helix axis</json:string><json:string>binding site</json:string><json:string>chemical shifts</json:string><json:string>large number</json:string><json:string>amino protons</json:string><json:string>molecular dynamics</json:string><json:string>xplor program</json:string><json:string>distance structures</json:string><json:string>relaxation matrix</json:string><json:string>covalent adducts</json:string><json:string>time step</json:string><json:string>nucleic</json:string><json:string>amino</json:string><json:string>right panel</json:string><json:string>proton restraints</json:string><json:string>noesy contour plot</json:string><json:string>charge delocalization</json:string><json:string>antitumor antibiotic</json:string><json:string>complex structure</json:string><json:string>minor groove sugar</json:string><json:string>control hairpin duplex</json:string><json:string>duplex level</json:string><json:string>phosphorus atoms</json:string><json:string>stereo views</json:string><json:string>central segment</json:string><json:string>covalent site</json:string><json:string>input distance restraints</json:string><json:string>imino protons</json:string><json:string>energy minimization</json:string><json:string>nucleic acid protons</json:string><json:string>minor groove width</json:string><json:string>noesy contour plots</json:string></teeft></keywords><author><json:item><name>Chin Hsiung Lin</name><affiliations><json:string>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</json:string></affiliations></json:item><json:item><name>Dinshaw J. Patel</name><affiliations><json:string>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>covalent duocarmycin-DNA complex</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>solution structure</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>duocarmycin alignment and directionality</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>intermolecular interactions in the minor groove</value></json:item></subject><arkIstex>ark:/67375/6H6-434K1VDN-Q</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Abstract: Duocarmycin A is an antitumour antibiotic that binds covalently to the minor groove N-3 position of adenine with sequence specificity for the 3′-adenine in a d(A-A-A-A) tract in duplex DNA. The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12+) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12+) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12+modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width andx-displacement parameters indicative of aB-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.</abstract><qualityIndicators><score>10</score><pdfWordCount>7553</pdfWordCount><pdfCharCount>48873</pdfCharCount><pdfVersion>1.1</pdfVersion><pdfPageCount>18</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>false</refBibsNative><abstractWordCount>263</abstractWordCount><abstractCharCount>1729</abstractCharCount><keywordCount>4</keywordCount></qualityIndicators><title>Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</title><pmid><json:string>7731041</json:string></pmid><pii><json:string>S0022-2836(85)70209-4</json:string></pii><genre><json:string>research-article</json:string></genre><host><title>Journal of Molecular Biology</title><language><json:string>unknown</json:string></language><publicationDate>1995</publicationDate><issn><json:string>0022-2836</json:string></issn><pii><json:string>S0022-2836(00)X0405-6</json:string></pii><volume>248</volume><issue>1</issue><pages><first>162</first><last>179</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>1000</json:string><json:string>1995</json:string></date><geogName></geogName><orgName><json:string>Brookhaven National Laboratory, Upton, New York</json:string><json:string>Keystone Co.</json:string><json:string>Biosym Technologies, Inc.</json:string><json:string>Yale University</json:string><json:string>NIH grant CA46778</json:string></orgName><orgName_funder><json:string>NIH grant CA46778</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Hiromitsu Saito</json:string><json:string>J. Patel</json:string><json:string>Dr Hiromitsu</json:string><json:string>The</json:string><json:string>PAGE Duocarmycin</json:string><json:string>A. Duocarmycin</json:string><json:string>A. Brunger</json:string></persName><placeName><json:string>Japan</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>Cosman et al., 1992</json:string><json:string>Boger et al., 1990</json:string><json:string>Lavery & Sklenar, 1988</json:string><json:string>Sklenar et al., 1986</json:string><json:string>Sugiyama et al., 1990</json:string><json:string>Takahashi et al., 1988</json:string><json:string>Santos et al., 1992</json:string><json:string>Weiss et al., 1984</json:string><json:string>Hurley et al., 1988</json:string><json:string>Boger et al., 1994</json:string><json:string>Plateau & Gueron, 1982</json:string><json:string>Boger et al., 1991b</json:string><json:string>Nelson et al., 1987</json:string><json:string>Lin et al., 1991</json:string><json:string>Ichimura et al., 1991</json:string><json:string>Lin & Hurley, 1992</json:string><json:string>Powers & Gorenstein, 1990</json:string><json:string>Krugh et al., 1989</json:string><json:string>Boyd et al., 1990</json:string><json:string>Lin & Patel, 1992</json:string><json:string>Reynolds et al., 1985</json:string><json:string>Scahill et al., 1990</json:string><json:string>Nilges et al., (1992)</json:string><json:string>reviewed by Warpehoski & Hurley, 1988</json:string><json:string>Sastry et al., 1995</json:string><json:string>Lin & Hurley, 1990</json:string><json:string>Sastry & Patel, 1993</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/6H6-434K1VDN-Q</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - biochemistry & molecular biology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - biochemistry & molecular biology</json:string></scienceMetrix><scopus><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Biology</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. psychologie</json:string></inist></categories><publicationDate>1995</publicationDate><copyrightDate>1995</copyrightDate><doi><json:string>10.1006/jmbi.1995.0209</json:string></doi><id>59C8080AC1AC1D4DDEE3300653A774572D8A68E0</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-434K1VDN-Q/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-434K1VDN-Q/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/6H6-434K1VDN-Q/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">ELSEVIER</publisher><availability><licence><p>©1995 Academic Press</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</p></availability><date>1995</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note type="content">Section title: Regular Article</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</title><author xml:id="author-0000"><persName><forename type="first">Chin Hsiung</forename><surname>Lin</surname></persName><affiliation>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Dinshaw J.</forename><surname>Patel</surname></persName><note type="correspondence"><p>Corresponding author</p></note><affiliation>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</affiliation></author><idno type="istex">59C8080AC1AC1D4DDEE3300653A774572D8A68E0</idno><idno type="ark">ark:/67375/6H6-434K1VDN-Q</idno><idno type="DOI">10.1006/jmbi.1995.0209</idno><idno type="PII">S0022-2836(85)70209-4</idno></analytic><monogr><title level="j">Journal of Molecular Biology</title><title level="j" type="abbrev">YJMBI</title><idno type="pISSN">0022-2836</idno><idno type="PII">S0022-2836(00)X0405-6</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1995"></date><biblScope unit="volume">248</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="162">162</biblScope><biblScope unit="page" to="179">179</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1995</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Duocarmycin A is an antitumour antibiotic that binds covalently to the minor groove N-3 position of adenine with sequence specificity for the 3′-adenine in a d(A-A-A-A) tract in duplex DNA. The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12+) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12+) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12+modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width andx-displacement parameters indicative of aB-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>covalent duocarmycin-DNA complex</term></item><item><term>solution structure</term></item><item><term>duocarmycin alignment and directionality</term></item><item><term>intermolecular interactions in the minor groove</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1995">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-434K1VDN-Q/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier converted-article found"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>YJMBI</jid><aid>70209</aid><ce:pii>S0022-2836(85)70209-4</ce:pii><ce:doi>10.1006/jmbi.1995.0209</ce:doi><ce:copyright type="full-transfer" year="1995">Academic Press</ce:copyright></item-info><head><ce:dochead><ce:textfn>Regular Article</ce:textfn></ce:dochead><ce:title>Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</ce:title><ce:author-group><ce:author><ce:given-name>Chin Hsiung</ce:given-name><ce:surname>Lin</ce:surname></ce:author><ce:author><ce:given-name>Dinshaw J.</ce:given-name><ce:surname>Patel</ce:surname><ce:cross-ref refid="FN1">*</ce:cross-ref></ce:author><ce:affiliation><ce:textfn>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</ce:textfn></ce:affiliation><ce:footnote id="FN1"><ce:label>f1</ce:label><ce:note-para>Corresponding author</ce:note-para></ce:footnote></ce:author-group><ce:date-received day="30" month="11" year="1994"></ce:date-received><ce:date-accepted day="30" month="1" year="1995"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Duocarmycin A is an antitumour antibiotic that binds covalently to the minor groove N-3 position of adenine with sequence specificity for the 3′-adenine in a d(A-A-A-A) tract in duplex DNA. The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12<ce:sup>+</ce:sup>) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12<ce:sup>+</ce:sup>) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12<ce:sup>+</ce:sup>modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width and<ce:italic>x</ce:italic>-displacement parameters indicative of a<ce:italic>B</ce:italic>-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>covalent duocarmycin-DNA complex</ce:text></ce:keyword><ce:keyword><ce:text>solution structure</ce:text></ce:keyword><ce:keyword><ce:text>duocarmycin alignment and directionality</ce:text></ce:keyword><ce:keyword><ce:text>intermolecular interactions in the minor groove</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Solution Structure of the Covalent Duocarmycin A-DNA Duplex Complex</title></titleInfo><name type="personal"><namePart type="given">Chin Hsiung</namePart><namePart type="family">Lin</namePart><affiliation>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dinshaw J.</namePart><namePart type="family">Patel</namePart><affiliation>Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.</affiliation><description>Corresponding author</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1995</dateIssued><copyrightDate encoding="w3cdtf">1995</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: Duocarmycin A is an antitumour antibiotic that binds covalently to the minor groove N-3 position of adenine with sequence specificity for the 3′-adenine in a d(A-A-A-A) tract in duplex DNA. The adenine ring becomes protonated on duocarmycin adduct formation resulting in charge delocalization over the purine ring system. We report on the solution structure of duocarmycin A bound site specifically to A12 (designated *12+) in the sequence context d(T3-T4-T5-T6)·d(A9-A10-A11-*A12+) within a hairpin duplex. The solution structure was solved based on a combined NMR-molecular dynamics study including NOE based intensity refinement. The A and B-rings of duocarmycin are positioned deep within the walls of the minor groove with the B-ring (which is furthest from the covalent linkage site) directed towards the 5′-end of the modified strand. Duocarmycin adopts an extended conformation and is aligned at ∼45° to the helix axis with its non-polar concave edges interacting with the floor of the minor groove while its polar edges are sandwiched within the walls of the minor groove. The T3·*A12+modification site pair forms a weak central Watson-Crick hydrogen bond in contrast to all A·T and G·C pairs, which align through standard Watson-Crick pairing in the complex. The helical parameters are consistent with a minimally perturbed right-handed duplex in the complex with minor groove width andx-displacement parameters indicative of aB-form helix. A striking feature of the complex is the positioning of duocarmycin A within the walls of the minor groove resulting in upfield shifts of the minor groove sugar protons, as well as backbone proton and phosphorus resonances in the DNA segment spanning the binding site.</abstract><note type="content">Section title: Regular Article</note><subject lang="en"><genre>Keywords</genre><topic>covalent duocarmycin-DNA complex</topic><topic>solution structure</topic><topic>duocarmycin alignment and directionality</topic><topic>intermolecular interactions in the minor groove</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Molecular Biology</title></titleInfo><titleInfo type="abbreviated"><title>YJMBI</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1995</dateIssued></originInfo><identifier type="ISSN">0022-2836</identifier><identifier type="PII">S0022-2836(00)X0405-6</identifier><part><date>1995</date><detail type="volume"><number>248</number><caption>vol.</caption></detail><detail type="issue"><number>1</number><caption>no.</caption></detail><extent unit="issue-pages"><start>1</start><end>201</end></extent><extent unit="pages"><start>162</start><end>179</end></extent></part></relatedItem><identifier type="istex">59C8080AC1AC1D4DDEE3300653A774572D8A68E0</identifier><identifier type="ark">ark:/67375/6H6-434K1VDN-Q</identifier><identifier type="DOI">10.1006/jmbi.1995.0209</identifier><identifier type="PII">S0022-2836(85)70209-4</identifier><accessCondition type="use and reproduction" contentType="copyright">©1995 Academic Press</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Academic Press, ©1995</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-434K1VDN-Q/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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