View source for 7rs8


==Crystal Structure of the ER-alpha Ligand-binding Domain (L372S, L536S) in complex with DMERI-16==
<StructureSection load='7rs8' size='340' side='right'caption='[[7rs8]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rs8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RS8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RS8 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7EI:(1R,2S,4R)-5-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-6-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-N-(2,2,2-trifluoroethyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide'>7EI</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></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=7rs8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rs8 OCA], [https://pdbe.org/7rs8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rs8 RCSB], [https://www.ebi.ac.uk/pdbsum/7rs8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rs8 ProSAT]</span></td></tr>
</table>
== Function ==
[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 ==
Efforts to improve estrogen receptor-alpha (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.

Dual-mechanism estrogen receptor inhibitors.,Min J, Nwachukwu JC, Min CK, Njeri JW, Srinivasan S, Rangarajan ES, Nettles CC, Sanabria Guillen V, Ziegler Y, Yan S, Carlson KE, Hou Y, Kim SH, Novick S, Pascal BD, Houtman R, Griffin PR, Izard T, Katzenellenbogen BS, Katzenellenbogen JA, Nettles KW Proc Natl Acad Sci U S A. 2021 Aug 31;118(35). pii: 2101657118. doi:, 10.1073/pnas.2101657118. PMID:34452998<ref>PMID:34452998</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7rs8" style="background-color:#fffaf0;"></div>

==See Also==
*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Griffin PR]]
[[Category: Houtman R]]
[[Category: Izard T]]
[[Category: Katzenellenbogen BS]]
[[Category: Katzenellenbogen JA]]
[[Category: Min CK]]
[[Category: Min J]]
[[Category: Nettles CC]]
[[Category: Nettles KW]]
[[Category: Njeri JW]]
[[Category: Nwachukwu JC]]
[[Category: Rangarajan ES]]
[[Category: Srinivasan S]]
[[Category: Yan S]]