6v8b - Revision history

OCA at 14:36, 6 March 2024

OCA — Wed, 06 Mar 2024 14:36:18 GMT

←Older revision		Revision as of 14:36, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='6v8b' size='340' side='right'caption='[[6v8b]], [[Resolution\|resolution]] 3.13Å' scene=''>		<StructureSection load='6v8b' size='340' side='right'caption='[[6v8b]], [[Resolution\|resolution]] 3.13Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6v8b]] is a 1 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=6V8B OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6V8B FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6v8b]] is a 1 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=6V8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V8B FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=QRY:4-(2-{[(1R)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino}ethyl)benzene-1-sulfonamide'>QRY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 3.13Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">EP300, P300 ([http://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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=QRY:4-(2-{[(1R)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino}ethyl)benzene-1-sulfonamide'>QRY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6v8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8b OCA], [~~http~~://pdbe.org/6v8b PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6v8b RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6v8b PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8b 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=6v8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8b OCA], [https://pdbe.org/6v8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v8b RCSB], [https://www.ebi.ac.uk/pdbsum/6v8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8b ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN]] Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:[~~http~~://omim.org/entry/613684 613684]]. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.<ref>PMID:15706485</ref>	+	[https://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN] Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:[https://omim.org/entry/613684 613684]. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.<ref>PMID:15706485</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN]] Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acetylates FOXO1 and enhances its transcriptional activity.<ref>PMID:11701890</ref> <ref>PMID:10733570</ref> <ref>PMID:11430825</ref> <ref>PMID:12586840</ref> <ref>PMID:12929931</ref> <ref>PMID:15186775</ref> <ref>PMID:15890677</ref> <ref>PMID:16762839</ref> <ref>PMID:18722353</ref>	+	[https://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN] Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acetylates FOXO1 and enhances its transcriptional activity.<ref>PMID:11701890</ref> <ref>PMID:10733570</ref> <ref>PMID:11430825</ref> <ref>PMID:12586840</ref> <ref>PMID:12929931</ref> <ref>PMID:15186775</ref> <ref>PMID:15890677</ref> <ref>PMID:16762839</ref> <ref>PMID:18722353</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	EP300 and CBP are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription via acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high-throughput screen of 191,000 compounds searching for EP300/CBP HAT inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including x-ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, AcCoA-competitive inhibitors, peptide-competitive inhibitors, and mixed/ allosteric inhibitors. The latter two classes of inhibitors have not been described before and the profiles of an exemplar of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA-competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of histone acetyltransferase inhibitors.	+

-	Early Drug Discovery Efforts Towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors.,Wilson JE, Huhn A, Gardberg AS, Poy F, Brucelle F, Vivat V, Patel G, Patel C, Cummings R, Sims R, Levell J, Audia JE, Bommi-Reddy A, Cantone N ChemMedChem. 2020 Mar 17. doi: 10.1002/cmdc.202000007. PMID:32181984<ref>PMID:32181984</ref>	+	==See Also==
-		+	*[[Histone acetyltransferase 3D structures\|Histone acetyltransferase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6v8b" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Gardberg~~, A S]]~~	+	[[Category: Gardberg AS]]
-	~~[[Category: Chromatin]]~~	+
-	~~[[Category: Epigenetic]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-inhibitor complex]]~~	+
-	~~[[Category: Writer~~]]	+

OCA at 10:45, 17 June 2020

OCA — Wed, 17 Jun 2020 10:45:45 GMT

←Older revision		Revision as of 10:45, 17 June 2020
Line 3:		Line 3:
	<StructureSection load='6v8b' size='340' side='right'caption='[[6v8b]], [[Resolution\|resolution]] 3.13Å' scene=''>		<StructureSection load='6v8b' size='340' side='right'caption='[[6v8b]], [[Resolution\|resolution]] 3.13Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6v8b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V8B OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6V8B FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6v8b]] is a 1 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=6V8B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6V8B FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=QRY:4-(2-{[(1R)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino}ethyl)benzene-1-sulfonamide'>QRY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=QRY:4-(2-{[(1R)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino}ethyl)benzene-1-sulfonamide'>QRY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6v8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8b OCA], [http://pdbe.org/6v8b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v8b RCSB], [http://www.ebi.ac.uk/pdbsum/6v8b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8b ProSAT]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">EP300, P300 ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6v8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8b OCA], [http://pdbe.org/6v8b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v8b RCSB], [http://www.ebi.ac.uk/pdbsum/6v8b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8b ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Gardberg, A S]]		[[Category: Gardberg, A S]]

OCA at 09:24, 1 April 2020

OCA — Wed, 01 Apr 2020 09:24:58 GMT

←Older revision		Revision as of 09:24, 1 April 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6v8b is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of the p300 acetyltransferase domain with AcCoA competitive inhibitor 1==
		+	<StructureSection load='6v8b' size='340' side='right'caption='[[6v8b]], [[Resolution\|resolution]] 3.13Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6v8b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6V8B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6V8B FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=QRY:4-(2-{[(1R)-2-(1H-indol-3-yl)-2-oxo-1-phenylethyl]amino}ethyl)benzene-1-sulfonamide'>QRY</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6v8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v8b OCA], [http://pdbe.org/6v8b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6v8b RCSB], [http://www.ebi.ac.uk/pdbsum/6v8b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6v8b ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN]] Note=Defects in EP300 may play a role in epithelial cancer. Note=Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. Defects in EP300 are the cause of Rubinstein-Taybi syndrome type 2 (RSTS2) [MIM:[http://omim.org/entry/613684 613684]]. A disorder characterized by craniofacial abnormalities, postnatal growth deficiency, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies. Some individuals with RSTS2 have less severe mental impairment, more severe microcephaly, and a greater degree of changes in facial bone structure than RSTS1 patients.<ref>PMID:15706485</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/EP300_HUMAN EP300_HUMAN]] Functions as histone acetyltransferase and regulates transcription via chromatin remodeling. Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation. Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Also functions as acetyltransferase for nonhistone targets. Acetylates 'Lys-131' of ALX1 and acts as its coactivator in the presence of CREBBP. Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function. Acetylates HDAC1 leading to its inactivation and modulation of transcription. Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2. Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein. In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Acetylates FOXO1 and enhances its transcriptional activity.<ref>PMID:11701890</ref> <ref>PMID:10733570</ref> <ref>PMID:11430825</ref> <ref>PMID:12586840</ref> <ref>PMID:12929931</ref> <ref>PMID:15186775</ref> <ref>PMID:15890677</ref> <ref>PMID:16762839</ref> <ref>PMID:18722353</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	EP300 and CBP are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription via acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high-throughput screen of 191,000 compounds searching for EP300/CBP HAT inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including x-ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, AcCoA-competitive inhibitors, peptide-competitive inhibitors, and mixed/ allosteric inhibitors. The latter two classes of inhibitors have not been described before and the profiles of an exemplar of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA-competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of histone acetyltransferase inhibitors.

-	~~Authors~~:	+	Early Drug Discovery Efforts Towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors.,Wilson JE, Huhn A, Gardberg AS, Poy F, Brucelle F, Vivat V, Patel G, Patel C, Cummings R, Sims R, Levell J, Audia JE, Bommi-Reddy A, Cantone N ChemMedChem. 2020 Mar 17. doi: 10.1002/cmdc.202000007. PMID:32181984<ref>PMID:32181984</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6v8b" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Gardberg, A S]]
		+	[[Category: Chromatin]]
		+	[[Category: Epigenetic]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-inhibitor complex]]
		+	[[Category: Writer]]

OCA at 14:14, 22 January 2020

OCA — Wed, 22 Jan 2020 14:14:11 GMT

←Older revision		Revision as of 14:14, 22 January 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6v8b is ON HOLD	+	The entry 6v8b is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "6v8b" [edit=sysop:move=sysop]

OCA — Wed, 18 Dec 2019 06:06:02 GMT

Protected "6v8b" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:06, 18 December 2019

OCA: New page: '''Unreleased structure''' The entry 6v8b is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 18 Dec 2019 06:06:01 GMT

New page: '''Unreleased structure''' The entry 6v8b is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6v8b is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]