Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol
Identifieur interne : 000A26 ( Main/Corpus ); précédent : 000A25; suivant : 000A27Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol
Auteurs : Johannes Von Langen ; Karl Einrich Fritzemeier ; Stephan Diekmann ; Alexander HillischSource :
- ChemBioChem [ 1439-4227 ] ; 2005-06-06.
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Abstract
We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.
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DOI: 10.1002/cbic.200400361
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In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. 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Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.</p></abstract><abstract xml:lang="en" style="graphical"><p>Steroid simulation: Molecular dynamics simulations of the glucocorticoid receptor protein (see molecular model) were used to explain measured binding affinities of this receptor for cortisol and four cortico‐ and sex steroids. Our approach is able to discriminate strongly and weakly binding compounds and explains the binding properties of several steroids at a molecular level.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>binding affinity</term></item><item><term>cortisol</term></item><item><term>molecular dynamics</term></item><item><term>receptors</term></item><item><term>steroids</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Full Paper</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-10-12">Received</change><change when="2005-06-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/D262305299C57535ACC1B9F7D745407EE9B6EE9C/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 version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>WILEY‐VCH Verlag</publisherName><publisherLoc>Weinheim</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1439-7633</doi><issn type="print">1439-4227</issn><issn type="electronic">1439-7633</issn><idGroup><id type="product" value="CBIC"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="CHEMBIOCHEM">ChemBioChem</title><title type="short">ChemBioChem</title></titleGroup></publicationMeta><publicationMeta level="part" position="60"><doi origin="wiley" registered="yes">10.1002/cbic.v6:6</doi><numberingGroup><numbering type="journalVolume" number="6">6</numbering><numbering type="journalIssue">6</numbering></numberingGroup><coverDate startDate="2005-06-06">June 6, 2005</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="26" status="forIssue"><doi origin="wiley" registered="yes">10.1002/cbic.200400361</doi><idGroup><id type="unit" value="CBIC200400361"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Full Paper</title></titleGroup><copyright ownership="publisher">Copyright © 2005 WILEY‐VCH Verlag GmbH & Co. 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In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.</i></p></abstract><abstract type="graphical" xml:lang="en"><p><b>Steroid simulation</b>: Molecular dynamics simulations of the glucocorticoid receptor protein (see molecular model) were used to explain measured binding affinities of this receptor for cortisol and four cortico‐ and sex steroids. Our approach is able to discriminate strongly and weakly binding compounds and explains the binding properties of several steroids at a molecular level.<blockFixed type="graphic"><mediaResourceGroup><mediaResource alt="image" eRights="yes" copyright="WILEY-VCH" href="urn:x-wiley:14394227:media:CBIC200400361:content"></mediaResource><mediaResource alt="thumbnail image" rendition="webLoRes" mimeType="image/gif" href=""></mediaResource><mediaResource alt="original image" rendition="webOriginal" mimeType="image/gif" href=""></mediaResource><mediaResource alt="magnified image" rendition="webHiRes" mimeType="image/gif" href=""></mediaResource></mediaResourceGroup></blockFixed></p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Molecular Basis of the Interaction Specificity between the Human Glucocorticoid Receptor and Its Endogenous Steroid Ligand Cortisol</title></titleInfo><name type="personal"><namePart type="given">Johannes</namePart><namePart type="family">von Langen</namePart><namePart type="termsOfAddress">Dr.</namePart><affiliation>Institute for Molecular Biotechnology, Beutenbergstrasse 11, 07745 Jena, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karl‐Heinrich</namePart><namePart type="family">Fritzemeier</namePart><namePart type="termsOfAddress">Dr.</namePart><affiliation>Schering AG, Müllerstrasse 178, 13342 Berlin, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephan</namePart><namePart type="family">Diekmann</namePart><namePart type="termsOfAddress">Prof. Dr.</namePart><affiliation>Institute for Molecular Biotechnology, Beutenbergstrasse 11, 07745 Jena, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexander</namePart><namePart type="family">Hillisch</namePart><namePart type="termsOfAddress">Dr.</namePart><affiliation>EnTec GmbH, Adolf‐Reichwein‐Strasse 20, 07745 Jena, Germany</affiliation><affiliation>Current address: Bayer HealthCare AG, Apratherweg 18a, 42096 Wuppertal, Germany, Fax: (+49) 202‐368149</affiliation><affiliation>E-mail: alexander.hillisch@bayerhealthcare.com</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>WILEY‐VCH Verlag</publisher><place><placeTerm type="text">Weinheim</placeTerm></place><dateIssued encoding="w3cdtf">2005-06-06</dateIssued><dateCaptured encoding="w3cdtf">2004-10-12</dateCaptured><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">7</extent><extent unit="tables">1</extent><extent unit="references">43</extent></physicalDescription><abstract lang="en">We analyzed the binding of five steroids to the human glucocorticoid receptor (hGR) experimentally as well as theoretically. In vitro, we measured the binding affinity of aldosterone, cortisol, estradiol, progesterone, and testosterone to hGR in competition with the ligand dexamethasone. The binding affinity relative to the endogenous ligand cortisol (100 %) is reduced for progesterone (22 %) and aldosterone (20 %) and is very weak for testosterone (1.5 %) and estradiol (0.2 %). In parallel, we constructed a homology model of the hGR ligand‐binding domain (LBD) based on the crystal structure of the human progesterone receptor (hPR). After docking the five steroids into the hGR model ligand‐binding pocket, we performed five separate 4‐ns molecular dynamics (MD) simulations with these complexes in order to study the complex structures. We calculated the binding affinities with two different approaches (MM/PBSA, FlexX) and compared them with the values of the experimentally determined relative binding affinities. Both theoretical methods allowed discrimination between strongly and weakly binding ligands and recognition of cortisol as the endogenous ligand of the hGR in silico. Cortisol binds most strongly due to a nearly perfect steric and electrostatic complementarity with the hGR binding pocket. Chemically similar ligands such as estradiol, testosterone, and progesterone also fit into the hGR binding pocket, but they are unable to form all those contacts with the amino acids of the protein that are necessary to yield a stable, transcriptionally active receptor conformation. Our analysis thus explains the selectivity of the human glucocorticoid receptor for its endogenous ligand cortisol at a molecular level.</abstract><abstract type="graphical" lang="en">Steroid simulation: Molecular dynamics simulations of the glucocorticoid receptor protein (see molecular model) were used to explain measured binding affinities of this receptor for cortisol and four cortico‐ and sex steroids. Our approach is able to discriminate strongly and weakly binding compounds and explains the binding properties of several steroids at a molecular level.</abstract><subject lang="en"><genre>Keywords</genre><topic>binding affinity</topic><topic>cortisol</topic><topic>molecular dynamics</topic><topic>receptors</topic><topic>steroids</topic></subject><relatedItem type="host"><titleInfo><title>ChemBioChem</title></titleInfo><titleInfo type="abbreviated"><title>ChemBioChem</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Supporting information for this article is available on the WWW under http://www.wiley‐vch.de/contents/jc_2268/2005/f400361_s.pdf or from the author.</note><subject><genre>article category</genre><topic>Full Paper</topic></subject><identifier type="ISSN">1439-4227</identifier><identifier type="eISSN">1439-7633</identifier><identifier type="DOI">10.1002/(ISSN)1439-7633</identifier><identifier type="PublisherID">CBIC</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>6</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>1110</start><end>1118</end><total>9</total></extent></part></relatedItem><identifier type="istex">D262305299C57535ACC1B9F7D745407EE9B6EE9C</identifier><identifier type="DOI">10.1002/cbic.200400361</identifier><identifier type="ArticleID">CBIC200400361</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2005 WILEY‐VCH Verlag GmbH & Co. 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