6w4k - Revision history

OCA at 14:16, 18 October 2023

OCA — Wed, 18 Oct 2023 14:16:41 GMT

←Older revision		Revision as of 14:16, 18 October 2023
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-	====	+	==Crystal structure of Lysine Specific Demethylase 1 (LSD1) with CC-90011==
-	<StructureSection load='6w4k' size='340' side='right'caption='[[6w4k]]' scene=''>	+	<StructureSection load='6w4k' size='340' side='right'caption='[[6w4k]], [[Resolution\|resolution]] 2.93Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6w4k]] 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=6W4K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W4K FirstGlance]. <br>
-	</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=6w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4k OCA], [https://pdbe.org/6w4k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w4k RCSB], [https://www.ebi.ac.uk/pdbsum/6w4k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4k ProSAT]</span></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]] 2.93Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=V0Y:4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile'>V0Y</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=6w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4k OCA], [https://pdbe.org/6w4k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w4k RCSB], [https://www.ebi.ac.uk/pdbsum/6w4k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4k ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/RCOR1_HUMAN RCOR1_HUMAN] Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation.<ref>PMID:11516394</ref> <ref>PMID:11171972</ref> <ref>PMID:12032298</ref> <ref>PMID:12399542</ref> <ref>PMID:12493763</ref> <ref>PMID:16140033</ref> <ref>PMID:16079794</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).
		+
		+	Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1).,Kanouni T, Severin C, Cho RW, Yuen NY, Xu J, Shi L, Lai C, Del Rosario JR, Stansfield RK, Lawton LN, Hosfield D, O'Connell S, Kreilein MM, Tavares-Greco P, Nie Z, Kaldor SW, Veal JM, Stafford JA, Chen YK J Med Chem. 2020 Dec 10;63(23):14522-14529. doi: 10.1021/acs.jmedchem.0c00978. , Epub 2020 Oct 9. PMID:33034194<ref>PMID:33034194</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6w4k" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Lysine-specific histone demethylase 3D structures\|Lysine-specific histone demethylase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Hosfield DJ]]

OCA at 15:54, 3 November 2021

OCA — Wed, 03 Nov 2021 15:54:12 GMT

←Older revision		Revision as of 15:54, 3 November 2021
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	<StructureSection load='6w4k' size='340' side='right'caption='[[6w4k]]' scene=''>		<StructureSection load='6w4k' size='340' side='right'caption='[[6w4k]]' 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= OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= 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=6w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4k OCA], [~~http~~://pdbe.org/6w4k PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6w4k RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6w4k PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4k ProSAT]</span></td></tr>	+	</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=6w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4k OCA], [https://pdbe.org/6w4k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w4k RCSB], [https://www.ebi.ac.uk/pdbsum/6w4k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4k ProSAT]</span></td></tr>
	</table>		</table>
	__TOC__		__TOC__

OCA at 08:14, 21 October 2020

OCA — Wed, 21 Oct 2020 08:14:57 GMT

←Older revision		Revision as of 08:14, 21 October 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6w4k ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='6w4k' size='340' side='right'caption='[[6w4k]]' scene=''>
-	~~Authors~~: ~~Hosfield, D~~.J.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure of Lysine Specific Demethylase 1 (LSD1) with CC~~-~~90011~~	+	</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=6w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w4k OCA], [http://pdbe.org/6w4k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w4k RCSB], [http://www.ebi.ac.uk/pdbsum/6w4k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w4k ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Hosfield, D.J~~]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 04:29, 19 August 2020

OCA — Wed, 19 Aug 2020 04:29:40 GMT

←Older revision		Revision as of 04:29, 19 August 2020
Line 5:		Line 5:
	Authors: Hosfield, D.J.		Authors: Hosfield, D.J.

-	Description: ~~Design~~ of ~~KDM4 Inhibitors~~ with ~~Antiproliferative Effects in Cancer Models~~	+	Description: Crystal structure of Lysine Specific Demethylase 1 (LSD1) with CC-90011
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Hosfield, D.J]]		[[Category: Hosfield, D.J]]

OCA at 18:16, 24 June 2020

OCA — Wed, 24 Jun 2020 18:16:07 GMT

←Older revision		Revision as of 18:16, 24 June 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6w4k is ON HOLD	+	The entry 6w4k is ON HOLD until Paper Publication

	Authors: Hosfield, D.J.		Authors: Hosfield, D.J.

OCA at 08:31, 17 June 2020

OCA — Wed, 17 Jun 2020 08:31:38 GMT

←Older revision		Revision as of 08:31, 17 June 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6w4k is ON HOLD ~~until sometime in the future~~	+	The entry 6w4k is ON HOLD

	Authors: Hosfield, D.J.		Authors: Hosfield, D.J.

-	Description: ~~Crystal Structure~~ of ~~Human LSD1 bound to QC6688~~	+	Description: Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Hosfield, D.J]]		[[Category: Hosfield, D.J]]

OCA at 08:22, 27 March 2020

OCA — Fri, 27 Mar 2020 08:22:23 GMT

←Older revision		Revision as of 08:22, 27 March 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6w4k is ON HOLD	+	The entry 6w4k is ON HOLD until sometime in the future

	Authors: Hosfield, D.J.		Authors: Hosfield, D.J.

OCA: Protected "6w4k" [edit=sysop:move=sysop]

OCA — Wed, 18 Mar 2020 08:34:38 GMT

Protected "6w4k" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:34, 18 March 2020

OCA: New page: '''Unreleased structure''' The entry 6w4k is ON HOLD Authors: Hosfield, D.J. Description: Crystal Structure of Human LSD1 bound to QC6688 Category: Unreleased Structures [[Category...

OCA — Wed, 18 Mar 2020 08:34:36 GMT

New page: '''Unreleased structure''' The entry 6w4k is ON HOLD Authors: Hosfield, D.J. Description: Crystal Structure of Human LSD1 bound to QC6688 Category: Unreleased Structures [[Category...

New page

'''Unreleased structure'''

The entry 6w4k is ON HOLD

Authors: Hosfield, D.J.

Description: Crystal Structure of Human LSD1 bound to QC6688
[[Category: Unreleased Structures]]
[[Category: Hosfield, D.J]]