7wnv

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Current revision (09:19, 17 October 2024) (edit) (undo)
 
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wnv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wnv OCA], [https://pdbe.org/7wnv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wnv RCSB], [https://www.ebi.ac.uk/pdbsum/7wnv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wnv 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=7wnv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wnv OCA], [https://pdbe.org/7wnv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wnv RCSB], [https://www.ebi.ac.uk/pdbsum/7wnv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wnv ProSAT]</span></td></tr>
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</table>
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== Function ==
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<div style="background-color:#fffaf0;">
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[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>
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== Publication Abstract from PubMed ==
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Endocrine therapy (ET) is a well-validated strategy for estrogen receptor alpha positive (ERalpha + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERalpha negative (ERalpha-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERalpha(Y537S) (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERalpha + breast cancer.
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X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.,Bai C, Lv Y, Xiong S, Wu S, Qi L, Ren S, Zhu M, Dong H, Shen H, Li Z, Zhu Y, Ye H, Hao H, Xiao Y, Xiang H, Luo G Bioorg Chem. 2023 Dec;141:106919. doi: 10.1016/j.bioorg.2023.106919. Epub 2023 , Oct 14. PMID:37871388<ref>PMID:37871388</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7wnv" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==

Current revision

Crystal structure of mutant estrogen receptor alpha Y537S in complex with CO9

PDB ID 7wnv

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

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