5aav - Revision history

OCA at 07:21, 1 May 2024

2024-05-01T07:21:12Z

←Older revision		Revision as of 07:21, 1 May 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5aav]] 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=5AAV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AAV FirstGlance]. <br>		<table><tr><td colspan='2'>[[5aav]] 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=5AAV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AAV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</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]] 1.95Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [https://pdbe.org/5aav PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [https://www.ebi.ac.uk/pdbsum/5aav PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aav 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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [https://pdbe.org/5aav PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [https://www.ebi.ac.uk/pdbsum/5aav PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aav 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;">
-	== Publication Abstract from PubMed ==
-	The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetra hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
-
-	Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetra hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.,De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z J Med Chem. 2015 Oct 7. PMID:26407012<ref>PMID:26407012</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5aav" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 04:48, 25 May 2023

2023-05-25T04:48:20Z

←Older revision		Revision as of 04:48, 25 May 2023
Line 3:		Line 3:
	<StructureSection load='5aav' size='340' side='right'caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>		<StructureSection load='5aav' size='340' side='right'caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5aav]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAV OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5AAV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5aav]] 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=5AAV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AAV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]~~</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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [https://pdbe.org/5aav PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [https://www.ebi.ac.uk/pdbsum/5aav PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aav ProSAT]</span></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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [~~http~~://pdbe.org/5aav PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5aav PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5aav 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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Almeida, C de]]~~	+	[[Category: Andrews DM]]
-	[[Category: Andrews~~, D M~~]]	+	[[Category: Ballard P]]
-	[[Category: Ballard, P]]	+	[[Category: Bradbury RH]]
-	[[Category: Bradbury~~, R H~~]]	+	[[Category: Buttar D]]
-	[[Category: Buttar, D]]	+	[[Category: Callis RJ]]
-	[[Category: Callis~~, R J~~]]	+	[[Category: Currie GS]]
-	[[Category: Currie~~, G S~~]]	+	[[Category: Curwen JO]]
-	[[Category: Curwen~~, J O~~]]	+	[[Category: Davies CD]]
-	[[Category: Davies~~, C D~~]]	+	[[Category: Donald CS]]
-	[[Category: Donald~~, C S~~]]	+	[[Category: Feron LJL]]
-	[[Category: Feron~~, L J.L~~]]	+	[[Category: Glossop SC]]
-	[[Category: Glossop~~, S C~~]]	+	[[Category: Hayter BR]]
-	[[Category: Hayter~~, B R~~]]	+	[[Category: Karoutchi G]]
-	[[Category: Karoutchi, G]]	+	[[Category: Lamont SG]]
-	[[Category: Lamont~~, S G~~]]	+	[[Category: MacFaul P]]
-	[[Category: MacFaul, P]]	+	[[Category: Moss T]]
-	[[Category: Moss, T]]	+	[[Category: Norman RA]]
-	[[Category: Norman~~, R A~~]]	+	[[Category: Pearson SE]]
-	[[Category: Pearson~~, S E~~]]	+	[[Category: Rabow AA]]
-	[[Category: Rabow~~, A A]]~~	+	[[Category: Tonge M]]
-	~~[[Category: Savi, C de~~]]	+	[[Category: Walker GE]]
-	[[Category: Tonge, M]]	+	[[Category: Weir HM]]
-	[[Category: Walker~~, G E~~]]	+	[[Category: Wilson Z]]
-	[[Category: Weir~~, H M~~]]	+	[[Category: De Almeida C]]
-	[[Category: Wilson, Z]]	+	[[Category: De Savi C]]
-	[[Category: ~~Azd9496~~]]	+
-	[[Category: ~~Breast cancer]]~~	+
-	~~[[Category: Estrogen receptor downregulator]]~~	+
-	~~[[Category: Fulvestrant]]~~	+
-	~~[[Category: Nuclear hormone receptor]]~~	+
-	~~[[Category: Signaling protein~~]]	+

OCA at 08:53, 26 June 2019

2019-06-26T08:53:00Z

←Older revision		Revision as of 08:53, 26 June 2019
Line 1:		Line 1:

	==Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist==		==Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist==
-	<StructureSection load='5aav' size='340' side='right' caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>	+	<StructureSection load='5aav' size='340' side='right'caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5aav]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AAV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5aav]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AAV FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]</td></tr>
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5aav" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5aav" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Estrogen receptor 3D structures\|Estrogen receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Almeida, C de]]		[[Category: Almeida, C de]]
	[[Category: Andrews, D M]]		[[Category: Andrews, D M]]

OCA at 10:09, 19 October 2016

2016-10-19T10:09:30Z

←Older revision		Revision as of 10:09, 19 October 2016
Line 1:		Line 1:
		+
	==Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist==		==Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist==
	<StructureSection load='5aav' size='340' side='right' caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>		<StructureSection load='5aav' size='340' side='right' caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]</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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [http://pdbe.org/5aav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [http://www.ebi.ac.uk/pdbsum/5aav PDBsum]</span></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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [http://pdbe.org/5aav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [http://www.ebi.ac.uk/pdbsum/5aav PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5aav ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 03:57, 16 October 2015

2015-10-16T03:57:53Z

←Older revision		Revision as of 03:57, 16 October 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist==
		+	<StructureSection load='5aav' size='340' side='right' caption='[[5aav]], [[Resolution\|resolution]] 1.95Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5aav]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AAV FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW5:(2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC+ACID'>GW5</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5aau\|5aau]]</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=5aav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aav OCA], [http://pdbe.org/5aav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aav RCSB], [http://www.ebi.ac.uk/pdbsum/5aav PDBsum]</span></td></tr>
		+	</table>
		+	== 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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetra hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.

-	~~The entry 5aav is ON HOLD until Paper Publication~~	+	Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetra hydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.,De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, Ballard P, Buttar D, Callis RJ, Currie GS, Curwen JO, Davies CD, Donald CS, Feron LJ, Gingell H, Glossop SC, Hayter BR, Hussain S, Karoutchi G, Lamont SG, MacFaul P, Moss TA, Pearson SE, Tonge M, Walker GE, Weir HM, Wilson Z J Med Chem. 2015 Oct 7. PMID:26407012<ref>PMID:26407012</ref>

-	~~Authors: Norman~~, ~~R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G~~.S., Curwen, J.O., Davies, C.D., de Savi, C., Donald, C.S., Feron, L.J.L., Glossop, S.C., Hayter, B.R., Karoutchi, G., Lamont, S.G., MacFaul, P., Moss, T., Pearson, S.E., Rabow, A.A., Tonge, M., Walker, G.E., Weir, H.M., Wilson, Z.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: Optimization of a novel binding motif to to (E)~~-3-(3,5-difluoro-4-(( 1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist	+	<div class="pdbe-citations 5aav" style="background-color:#fffaf0;"></div>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	== References ==
-	~~[[Category: Walker, G.E]]~~	+	<references/>
-	~~[[Category: Rabow, A.A]]~~	+	__TOC__
-	~~[[Category: Wilson, Z]]~~	+	</StructureSection>
-	~~[[Category: Curwen, J.O]]~~	+	[[Category: Almeida, C de]]
-	[[Category: ~~Moss~~, T]]	+	[[Category: Andrews, D M]]
-	[[Category: ~~Karoutchi~~, G]]	+
	[[Category: Ballard, P]]		[[Category: Ballard, P]]
-	[[Category: ~~Glossop~~, ~~S.C]]~~	+	[[Category: Bradbury, R H]]
-	~~[[Category: Davies, C.D]]~~	+
-	~~[[Category: De Almeida, C~~]]	+
	[[Category: Buttar, D]]		[[Category: Buttar, D]]
-	[[Category: ~~Donald~~, C.S]]	+	[[Category: Callis, R J]]
-	[[Category: ~~Andrews~~, D.M]]	+	[[Category: Currie, G S]]
-	[[Category: ~~De Savi~~, C]]	+	[[Category: Curwen, J O]]
-	[[Category: ~~Callis~~, R.J]]	+	[[Category: Davies, C D]]
-	[[Category: Hayter, B.R]]	+	[[Category: Donald, C S]]
-	[[Category: ~~Macfaul~~, P]]	+	[[Category: Feron, L J.L]]
-	[[Category: ~~Feron~~, ~~L.J.L~~]]	+	[[Category: Glossop, S C]]
-	[[Category: Norman, R.A]]	+	[[Category: Hayter, B R]]
-	[[Category: ~~Weir~~, ~~H.M~~]]	+	[[Category: Karoutchi, G]]
		+	[[Category: Lamont, S G]]
		+	[[Category: MacFaul, P]]
		+	[[Category: Moss, T]]
		+	[[Category: Norman, R A]]
		+	[[Category: Pearson, S E]]
		+	[[Category: Rabow, A A]]
		+	[[Category: Savi, C de]]
	[[Category: Tonge, M]]		[[Category: Tonge, M]]
-	[[Category: ~~Lamont~~, S.G]]	+	[[Category: Walker, G E]]
-	[[Category: ~~Pearson~~, ~~S.E~~]]	+	[[Category: Weir, H M]]
-	[[Category: ~~Currie~~, ~~G.S~~]]	+	[[Category: Wilson, Z]]
-	[[Category: ~~Bradbury, R.H~~]]	+	[[Category: Azd9496]]
		+	[[Category: Breast cancer]]
		+	[[Category: Estrogen receptor downregulator]]
		+	[[Category: Fulvestrant]]
		+	[[Category: Nuclear hormone receptor]]
		+	[[Category: Signaling protein]]

OCA at 10:27, 7 October 2015

2015-10-07T10:27:56Z

←Older revision		Revision as of 10:27, 7 October 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5aav is ON HOLD	+	The entry 5aav is ON HOLD until Paper Publication

	Authors: Norman, R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G.S., Curwen, J.O., Davies, C.D., de Savi, C., Donald, C.S., Feron, L.J.L., Glossop, S.C., Hayter, B.R., Karoutchi, G., Lamont, S.G., MacFaul, P., Moss, T., Pearson, S.E., Rabow, A.A., Tonge, M., Walker, G.E., Weir, H.M., Wilson, Z.		Authors: Norman, R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G.S., Curwen, J.O., Davies, C.D., de Savi, C., Donald, C.S., Feron, L.J.L., Glossop, S.C., Hayter, B.R., Karoutchi, G., Lamont, S.G., MacFaul, P., Moss, T., Pearson, S.E., Rabow, A.A., Tonge, M., Walker, G.E., Weir, H.M., Wilson, Z.

OCA: Protected "5aav" [edit=sysop:move=sysop]

2015-08-05T17:36:42Z

Protected "5aav" [edit=sysop:move=sysop]

←Older revision

Revision as of 17:36, 5 August 2015

OCA: New page: '''Unreleased structure''' The entry 5aav is ON HOLD Authors: Norman, R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G.S., Curwen, J...

2015-08-05T17:36:41Z

New page: '''Unreleased structure''' The entry 5aav is ON HOLD Authors: Norman, R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G.S., Curwen, J...

New page

'''Unreleased structure'''

The entry 5aav is ON HOLD

Authors: Norman, R.A., Bradbury, R.H., de Almeida, C., Andrews, D.M., Ballard, P., Buttar, D., Callis, R.J., Currie, G.S., Curwen, J.O., Davies, C.D., de Savi, C., Donald, C.S., Feron, L.J.L., Glossop, S.C., Hayter, B.R., Karoutchi, G., Lamont, S.G., MacFaul, P., Moss, T., Pearson, S.E., Rabow, A.A., Tonge, M., Walker, G.E., Weir, H.M., Wilson, Z.

Description: Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-(( 1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist
[[Category: Unreleased Structures]]
[[Category: Walker, G.E]]
[[Category: Rabow, A.A]]
[[Category: Wilson, Z]]
[[Category: Curwen, J.O]]
[[Category: Moss, T]]
[[Category: Karoutchi, G]]
[[Category: Ballard, P]]
[[Category: Glossop, S.C]]
[[Category: Davies, C.D]]
[[Category: De Almeida, C]]
[[Category: Buttar, D]]
[[Category: Donald, C.S]]
[[Category: Andrews, D.M]]
[[Category: De Savi, C]]
[[Category: Callis, R.J]]
[[Category: Hayter, B.R]]
[[Category: Macfaul, P]]
[[Category: Feron, L.J.L]]
[[Category: Norman, R.A]]
[[Category: Weir, H.M]]
[[Category: Tonge, M]]
[[Category: Lamont, S.G]]
[[Category: Pearson, S.E]]
[[Category: Currie, G.S]]
[[Category: Bradbury, R.H]]