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==Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with an N-trifluoroethyl 4-chlorobenzyl OBHS-N derivative==
==Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with an N-trifluoroethyl 4-chlorobenzyl OBHS-N derivative==
<StructureSection load='5kd9' size='340' side='right' caption='[[5kd9]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
<StructureSection load='5kd9' size='340' side='right'caption='[[5kd9]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5kd9]] is a 4 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5bq4 5bq4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KD9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KD9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5kd9]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5bq4 5bq4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KD9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KD9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OBT:(1S,2R,4S)-N-(4-CHLOROPHENYL)-5,6-BIS(4-HYDROXYPHENYL)-N-(2,2,2-TRIFLUOROETHYL)-7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-SULFONAMIDE'>OBT</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5kcc|5kcc]], [[5kcd|5kcd]], [[5kcf|5kcf]], [[5kct|5kct]], [[5kcu|5kcu]], [[5kcw|5kcw]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OBT:(1S,2R,4S)-N-(4-CHLOROPHENYL)-5,6-BIS(4-HYDROXYPHENYL)-N-(2,2,2-TRIFLUOROETHYL)-7-OXABICYCLO[2.2.1]HEPT-5-ENE-2-SULFONAMIDE'>OBT</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kd9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kd9 OCA], [http://pdbe.org/5kd9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kd9 RCSB], [http://www.ebi.ac.uk/pdbsum/5kd9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kd9 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kd9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kd9 OCA], [https://pdbe.org/5kd9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kd9 RCSB], [https://www.ebi.ac.uk/pdbsum/5kd9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kd9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/ESR1_HUMAN ESR1_HUMAN]] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</ref>
[https://www.uniprot.org/uniprot/ESR1_HUMAN ESR1_HUMAN] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-alpha (ERalpha)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERalpha through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor, and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERalpha-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.


Full antagonism of the estrogen receptor without a prototypical ligand side chain.,Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW Nat Chem Biol. 2017 Jan;13(1):111-118. doi: 10.1038/nchembio.2236. Epub 2016 Nov , 21. PMID:27870835<ref>PMID:27870835</ref>
==See Also==
 
*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5kd9" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Boonmuen, N]]
[[Category: Homo sapiens]]
[[Category: Bruno, N E]]
[[Category: Large Structures]]
[[Category: Dharmarajan, V]]
[[Category: Boonmuen N]]
[[Category: Frasor, J]]
[[Category: Bruno NE]]
[[Category: Goswami, D]]
[[Category: Dharmarajan V]]
[[Category: Griffin, P R]]
[[Category: Frasor J]]
[[Category: Kastrati, I]]
[[Category: Goswami D]]
[[Category: Katzenellenbogen, B S]]
[[Category: Griffin PR]]
[[Category: Katzenellenbogen, J A]]
[[Category: Kastrati I]]
[[Category: Min, J]]
[[Category: Katzenellenbogen BS]]
[[Category: Nettles, K W]]
[[Category: Katzenellenbogen JA]]
[[Category: Novick, S]]
[[Category: Min J]]
[[Category: Nowak, J]]
[[Category: Nettles KW]]
[[Category: Nwachukwu, J C]]
[[Category: Novick S]]
[[Category: Srinivasan, S]]
[[Category: Nowak J]]
[[Category: Zhao, Y]]
[[Category: Nwachukwu JC]]
[[Category: Zhou, H B]]
[[Category: Srinivasan S]]
[[Category: Ligand binding]]
[[Category: Zhao Y]]
[[Category: Nuclear receptor]]
[[Category: Zhou HB]]
[[Category: Protein-ligand complex]]
[[Category: Transcription]]
[[Category: Transcription factor]]

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