Estrogen receptor residues required for stereospecific ligand recognition and activation.
Identifieur interne : 002724 ( PubMed/Corpus ); précédent : 002723; suivant : 002725Estrogen receptor residues required for stereospecific ligand recognition and activation.
Auteurs : W P Bocchinfuso ; K S KorachSource :
- Molecular endocrinology (Baltimore, Md.) [ 0888-8809 ] ; 1997.
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Receptors, Estrogen.
- chemical , metabolism : Estrogens, Non-Steroidal, Indenes, Receptors, Estrogen.
- Animals, Binding Sites, Ligands, Mice, Protein Conformation, Saccharomyces cerevisiae, Stereoisomerism.
Abstract
The mouse estrogen receptor (mER) has been shown to exhibit stereospecific binding of certain stilbene estrogen agonists. The region of the mER involved in the stereochemical recognition of ligands was further defined using a stilbene isomer, Indenestrol B (IB). The IB compound has a chiral carbon bearing an ethyl substituent, and the wild type uterine mER has been shown to bind the enantiomers, IB-S and IB-R, with similar affinity. The wild type mER expressed in yeast exhibited a very minor preference for IB-S in transactivation (1.5-fold lower half-maximal dose than IB-R). The IB enantiomers could then be used to determine whether stereochemically distinct compounds with similar transcriptional activity utilize different amino acids in AF-2 for transactivation. Mutant mERs with glycine substitutions at Met521, His528, Met532, and Val537 were expressed in yeast and measured for IB-S- and IB-R-induced transactivation and ligand binding. The M532G mER showed a 124-fold and 50-fold reduction in transactivation induced by IB-S and IB-R, respectively, without a corresponding change in their ligand-binding affinities. Therefore, Met532 is required for transactivation induced by both IB enantiomers but does not discriminate based on stereospecificity. In contrast, the H528G mER displayed a gross change in stereospecific ligand recognition as illustrated by a 110-fold reduction in transactivation by IB-S and only a 8.8-fold decrease in activity by IB-R. As a result, H528G mER displayed a switch in ligand preference such that IB-R was now 8-fold more active than IB-S in transactivation. Therefore, His528 appears largely involved in transactivation specifically induced by IB-S but has a minimal influence in IB-S ligand binding. The remaining mutant mERs displayed wild type ligand binding and transactivation properties for the IB enantiomers illustrating no stereospecific recognition. These results imply that individual IB enantiomers bind to the mER with similar affinity but utilize at least one different amino acid within the AF-2 domain for signal transduction. The binding of stereochemically distinct ligands may alter the tertiary structure of the mER and cause repositioning of the AF-2 region that mediates transcription of specific genes and/or affect the binding of receptor-associated proteins, such as coactivators, which could influence transcription.
DOI: 10.1210/mend.11.5.9931
PubMed: 9139802
Links to Exploration step
pubmed:9139802Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Estrogen receptor residues required for stereospecific ligand recognition and activation.</title>
<author><name sortKey="Bocchinfuso, W P" sort="Bocchinfuso, W P" uniqKey="Bocchinfuso W" first="W P" last="Bocchinfuso">W P Bocchinfuso</name>
<affiliation><nlm:affiliation>Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Korach, K S" sort="Korach, K S" uniqKey="Korach K" first="K S" last="Korach">K S Korach</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="1997">1997</date>
<idno type="RBID">pubmed:9139802</idno>
<idno type="pmid">9139802</idno>
<idno type="doi">10.1210/mend.11.5.9931</idno>
<idno type="wicri:Area/PubMed/Corpus">002724</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002724</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Estrogen receptor residues required for stereospecific ligand recognition and activation.</title>
<author><name sortKey="Bocchinfuso, W P" sort="Bocchinfuso, W P" uniqKey="Bocchinfuso W" first="W P" last="Bocchinfuso">W P Bocchinfuso</name>
<affiliation><nlm:affiliation>Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Korach, K S" sort="Korach, K S" uniqKey="Korach K" first="K S" last="Korach">K S Korach</name>
</author>
</analytic>
<series><title level="j">Molecular endocrinology (Baltimore, Md.)</title>
<idno type="ISSN">0888-8809</idno>
<imprint><date when="1997" type="published">1997</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Binding Sites</term>
<term>Estrogens, Non-Steroidal (metabolism)</term>
<term>Indenes (metabolism)</term>
<term>Ligands</term>
<term>Mice</term>
<term>Protein Conformation</term>
<term>Receptors, Estrogen (chemistry)</term>
<term>Receptors, Estrogen (metabolism)</term>
<term>Saccharomyces cerevisiae</term>
<term>Stereoisomerism</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Receptors, Estrogen</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Estrogens, Non-Steroidal</term>
<term>Indenes</term>
<term>Receptors, Estrogen</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Binding Sites</term>
<term>Ligands</term>
<term>Mice</term>
<term>Protein Conformation</term>
<term>Saccharomyces cerevisiae</term>
<term>Stereoisomerism</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The mouse estrogen receptor (mER) has been shown to exhibit stereospecific binding of certain stilbene estrogen agonists. The region of the mER involved in the stereochemical recognition of ligands was further defined using a stilbene isomer, Indenestrol B (IB). The IB compound has a chiral carbon bearing an ethyl substituent, and the wild type uterine mER has been shown to bind the enantiomers, IB-S and IB-R, with similar affinity. The wild type mER expressed in yeast exhibited a very minor preference for IB-S in transactivation (1.5-fold lower half-maximal dose than IB-R). The IB enantiomers could then be used to determine whether stereochemically distinct compounds with similar transcriptional activity utilize different amino acids in AF-2 for transactivation. Mutant mERs with glycine substitutions at Met521, His528, Met532, and Val537 were expressed in yeast and measured for IB-S- and IB-R-induced transactivation and ligand binding. The M532G mER showed a 124-fold and 50-fold reduction in transactivation induced by IB-S and IB-R, respectively, without a corresponding change in their ligand-binding affinities. Therefore, Met532 is required for transactivation induced by both IB enantiomers but does not discriminate based on stereospecificity. In contrast, the H528G mER displayed a gross change in stereospecific ligand recognition as illustrated by a 110-fold reduction in transactivation by IB-S and only a 8.8-fold decrease in activity by IB-R. As a result, H528G mER displayed a switch in ligand preference such that IB-R was now 8-fold more active than IB-S in transactivation. Therefore, His528 appears largely involved in transactivation specifically induced by IB-S but has a minimal influence in IB-S ligand binding. The remaining mutant mERs displayed wild type ligand binding and transactivation properties for the IB enantiomers illustrating no stereospecific recognition. These results imply that individual IB enantiomers bind to the mER with similar affinity but utilize at least one different amino acid within the AF-2 domain for signal transduction. The binding of stereochemically distinct ligands may alter the tertiary structure of the mER and cause repositioning of the AF-2 region that mediates transcription of specific genes and/or affect the binding of receptor-associated proteins, such as coactivators, which could influence transcription.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">9139802</PMID>
<DateCompleted><Year>1997</Year>
<Month>07</Month>
<Day>08</Day>
</DateCompleted>
<DateRevised><Year>2012</Year>
<Month>11</Month>
<Day>15</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Print">0888-8809</ISSN>
<JournalIssue CitedMedium="Print"><Volume>11</Volume>
<Issue>5</Issue>
<PubDate><Year>1997</Year>
<Month>May</Month>
</PubDate>
</JournalIssue>
<Title>Molecular endocrinology (Baltimore, Md.)</Title>
<ISOAbbreviation>Mol. Endocrinol.</ISOAbbreviation>
</Journal>
<ArticleTitle>Estrogen receptor residues required for stereospecific ligand recognition and activation.</ArticleTitle>
<Pagination><MedlinePgn>587-94</MedlinePgn>
</Pagination>
<Abstract><AbstractText>The mouse estrogen receptor (mER) has been shown to exhibit stereospecific binding of certain stilbene estrogen agonists. The region of the mER involved in the stereochemical recognition of ligands was further defined using a stilbene isomer, Indenestrol B (IB). The IB compound has a chiral carbon bearing an ethyl substituent, and the wild type uterine mER has been shown to bind the enantiomers, IB-S and IB-R, with similar affinity. The wild type mER expressed in yeast exhibited a very minor preference for IB-S in transactivation (1.5-fold lower half-maximal dose than IB-R). The IB enantiomers could then be used to determine whether stereochemically distinct compounds with similar transcriptional activity utilize different amino acids in AF-2 for transactivation. Mutant mERs with glycine substitutions at Met521, His528, Met532, and Val537 were expressed in yeast and measured for IB-S- and IB-R-induced transactivation and ligand binding. The M532G mER showed a 124-fold and 50-fold reduction in transactivation induced by IB-S and IB-R, respectively, without a corresponding change in their ligand-binding affinities. Therefore, Met532 is required for transactivation induced by both IB enantiomers but does not discriminate based on stereospecificity. In contrast, the H528G mER displayed a gross change in stereospecific ligand recognition as illustrated by a 110-fold reduction in transactivation by IB-S and only a 8.8-fold decrease in activity by IB-R. As a result, H528G mER displayed a switch in ligand preference such that IB-R was now 8-fold more active than IB-S in transactivation. Therefore, His528 appears largely involved in transactivation specifically induced by IB-S but has a minimal influence in IB-S ligand binding. The remaining mutant mERs displayed wild type ligand binding and transactivation properties for the IB enantiomers illustrating no stereospecific recognition. These results imply that individual IB enantiomers bind to the mER with similar affinity but utilize at least one different amino acid within the AF-2 domain for signal transduction. The binding of stereochemically distinct ligands may alter the tertiary structure of the mER and cause repositioning of the AF-2 region that mediates transcription of specific genes and/or affect the binding of receptor-associated proteins, such as coactivators, which could influence transcription.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bocchinfuso</LastName>
<ForeName>W P</ForeName>
<Initials>WP</Initials>
<AffiliationInfo><Affiliation>Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Korach</LastName>
<ForeName>K S</ForeName>
<Initials>KS</Initials>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
</PublicationTypeList>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Mol Endocrinol</MedlineTA>
<NlmUniqueID>8801431</NlmUniqueID>
<ISSNLinking>0888-8809</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D004968">Estrogens, Non-Steroidal</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D007192">Indenes</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D008024">Ligands</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011960">Receptors, Estrogen</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>4A464K3BSI</RegistryNumber>
<NameOfSubstance UI="C047437">indenestrol</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004968" MajorTopicYN="N">Estrogens, Non-Steroidal</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D007192" MajorTopicYN="N">Indenes</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008024" MajorTopicYN="N">Ligands</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011487" MajorTopicYN="Y">Protein Conformation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011960" MajorTopicYN="N">Receptors, Estrogen</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D012441" MajorTopicYN="N">Saccharomyces cerevisiae</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013237" MajorTopicYN="N">Stereoisomerism</DescriptorName>
</MeshHeading>
</MeshHeadingList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>1997</Year>
<Month>5</Month>
<Day>1</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>1997</Year>
<Month>5</Month>
<Day>1</Day>
<Hour>0</Hour>
<Minute>1</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>1997</Year>
<Month>5</Month>
<Day>1</Day>
<Hour>0</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">9139802</ArticleId>
<ArticleId IdType="doi">10.1210/mend.11.5.9931</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/PubMed/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002724 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd -nk 002724 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= MersV1 |flux= PubMed |étape= Corpus |type= RBID |clé= pubmed:9139802 |texte= Estrogen receptor residues required for stereospecific ligand recognition and activation. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/RBID.i -Sk "pubmed:9139802" \ | HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a MersV1
This area was generated with Dilib version V0.6.33. |