6zos - Revision history

OCA at 11:55, 1 February 2024

2024-02-01T11:55:45Z

← Older revision		Revision as of 11:55, 1 February 2024
Line 3:		Line 3:
	<StructureSection load='6zos' size='340' side='right'caption='[[6zos]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6zos' size='340' side='right'caption='[[6zos]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6zos]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZOS FirstGlance]. <br>		<table><tr><td colspan='2'>[[6zos]] is a 2 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=6ZOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZOS FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QNK:6-[(6~{S},8~{R})-7-[(1-fluoranylcyclopropyl)methyl]-8-methyl-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-~{N}-[1-(3-fluoranylpropyl)azetidin-3-yl]pyridin-3-amine'>QNK</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]] 2Å</td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ESR1, ESR, NR3A1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QNK:6-[(6~{S},8~{R})-7-[(1-fluoranylcyclopropyl)methyl]-8-methyl-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-~{N}-[1-(3-fluoranylpropyl)azetidin-3-yl]pyridin-3-amine'>QNK</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=6zos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zos OCA], [https://pdbe.org/6zos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zos RCSB], [https://www.ebi.ac.uk/pdbsum/6zos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zos 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=6zos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zos OCA], [https://pdbe.org/6zos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zos RCSB], [https://www.ebi.ac.uk/pdbsum/6zos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zos ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== 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>		[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Breed, J]]		[[Category: Breed J]]
	~~[[Category: Gene regulation]]~~
	~~[[Category: Oestrogen receptor~~]]

OCA at 07:35, 19 January 2022

2022-01-19T07:35:34Z

← Older revision		Revision as of 07:35, 19 January 2022
Line 1:		Line 1:

	==Oestrogen receptor ligand binding domain in complex with compound 18==		==Oestrogen receptor ligand binding domain in complex with compound 18==
	<StructureSection load='6zos' size='340' side='right'caption='[[6zos]]' scene=''>		<StructureSection load='6zos' size='340' side='right'caption='[[6zos]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZOS OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6ZOS FirstGlance]. <br>		<table><tr><td colspan='2'>[[6zos]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZOS FirstGlance]. <br>
	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6zos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zos OCA], [~~http~~://pdbe.org/6zos PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6zos RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6zos PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6zos ProSAT]</span></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QNK:6-[(6~{S},8~{R})-7-[(1-fluoranylcyclopropyl)methyl]-8-methyl-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-~{N}-[1-(3-fluoranylpropyl)azetidin-3-yl]pyridin-3-amine'>QNK</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">ESR1, ESR, NR3A1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6zos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zos OCA], [https://pdbe.org/6zos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zos RCSB], [https://www.ebi.ac.uk/pdbsum/6zos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zos ProSAT]</span></td></tr>
	</table>		</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 ==
			Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER(+) breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)- 6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERalpha in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

			Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.,Scott JS, Moss TA, Balazs A, Barlaam B, Breed J, Carbajo RJ, Chiarparin E, Davey PRJ, Delpuech O, Fawell S, Fisher DI, Gagrica S, Gangl ET, Grebe T, Greenwood RD, Hande S, Hatoum-Mokdad H, Herlihy K, Hughes S, Hunt TA, Huynh H, Janbon SLM, Johnson T, Kavanagh S, Klinowska T, Lawson M, Lister AS, Marden S, McGinnity DF, Morrow CJ, Nissink JWM, O'Donovan DH, Peng B, Polanski R, Stead DS, Stokes S, Thakur K, Throner SR, Tucker MJ, Varnes J, Wang H, Wilson DM, Wu D, Wu Y, Yang B, Yang W J Med Chem. 2020 Dec 10;63(23):14530-14559. doi: 10.1021/acs.jmedchem.0c01163., Epub 2020 Sep 29. PMID:32910656<ref>PMID:32910656</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 6zos" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Estrogen receptor 3D structures\|Estrogen receptor 3D structures]]
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Breed J]]		[[Category: Breed, J]]
			[[Category: Gene regulation]]
			[[Category: Oestrogen receptor]]

OCA at 08:12, 20 January 2021

2021-01-20T08:12:53Z

← Older revision		Revision as of 08:12, 20 January 2021
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 6zos is ~~ON HOLD until Paper Publication~~		==Oestrogen receptor ligand binding domain in complex with compound 18==
			<StructureSection load='6zos' size='340' side='right'caption='[[6zos]]' scene=''>
	~~Authors:~~		== Structural highlights ==
			<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZOS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZOS FirstGlance]. <br>
	~~Description~~:		</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zos OCA], [http://pdbe.org/6zos PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zos RCSB], [http://www.ebi.ac.uk/pdbsum/6zos PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zos ProSAT]</span></td></tr>
	[[Category: ~~Unreleased Structures~~]]		</table>
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Breed J]]

OCA at 03:57, 5 August 2020

2020-08-05T03:57:09Z

← Older revision		Revision as of 03:57, 5 August 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 6zos is ON HOLD		The entry 6zos is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6zos" [edit=sysop:move=sysop]

2020-07-22T08:08:20Z

Protected "6zos" [edit=sysop:move=sysop]

← Older revision	Revision as of 08:08, 22 July 2020
(No difference)

OCA: New page: '''Unreleased structure''' The entry 6zos is ON HOLD Authors: Description: Category: Unreleased Structures

2020-07-22T08:08:18Z

New page: '''Unreleased structure''' The entry 6zos is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6zos is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]