6maj - Revision history

OCA at 16:38, 22 January 2020

OCA — Wed, 22 Jan 2020 16:38:34 GMT

←Older revision		Revision as of 16:38, 22 January 2020
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	<StructureSection load='6maj' size='340' side='right'caption='[[6maj]], [[Resolution\|resolution]] 2.14Å' scene=''>		<StructureSection load='6maj' size='340' side='right'caption='[[6maj]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6maj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MAJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MAJ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6maj]] 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=6MAJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MAJ FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JAV:4-fluoro-N-[(3-hydroxyphenyl)sulfonyl]-5-methyl[1,1-biphenyl]-3-carbohydrazide'>JAV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JAV:4-fluoro-N-[(3-hydroxyphenyl)sulfonyl]-5-methyl[1,1-biphenyl]-3-carbohydrazide'>JAV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KAT7, HBO1, HBOa, MYST2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), BRD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </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=6maj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6maj OCA], [http://pdbe.org/6maj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6maj RCSB], [http://www.ebi.ac.uk/pdbsum/6maj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6maj 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=6maj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6maj OCA], [http://pdbe.org/6maj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6maj RCSB], [http://www.ebi.ac.uk/pdbsum/6maj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6maj ProSAT]</span></td></tr>
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	</StructureSection>		</StructureSection>
	[[Category: Histone acetyltransferase]]		[[Category: Histone acetyltransferase]]
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Dawson, M]]		[[Category: Dawson, M]]

OCA at 09:06, 25 December 2019

OCA — Wed, 25 Dec 2019 09:06:12 GMT

←Older revision		Revision as of 09:06, 25 December 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6maj is ~~ON HOLD~~ ~~until Dec 28 2020~~	+	==HBO1 is required for the maintenance of leukaemia stem cells==
		+	<StructureSection load='6maj' size='340' side='right'caption='[[6maj]], [[Resolution\|resolution]] 2.14Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6maj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MAJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MAJ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=JAV:4-fluoro-N-[(3-hydroxyphenyl)sulfonyl]-5-methyl[1,1-biphenyl]-3-carbohydrazide'>JAV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </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=6maj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6maj OCA], [http://pdbe.org/6maj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6maj RCSB], [http://www.ebi.ac.uk/pdbsum/6maj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6maj ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/KAT7_HUMAN KAT7_HUMAN]] Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Through chromatin acetylation it may regulate DNA replication and act as a coactivator of TP53-dependent transcription. Acts as a coactivator of the licensing factor CDT1 (PubMed:18832067). Specifically represses AR-mediated transcription.<ref>PMID:10438470</ref> <ref>PMID:10930412</ref> <ref>PMID:11278932</ref> <ref>PMID:16387653</ref> <ref>PMID:18832067</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

-	~~Authors: Ren, B~~., ~~Peat~~, T.S., ~~Monahan~~, B., ~~Dawson~~, M., Street, I.	+	HBO1 is required for the maintenance of leukaemia stem cells.,MacPherson L, Anokye J, Yeung MM, Lam EYN, Chan YC, Weng CF, Yeh P, Knezevic K, Butler MS, Hoegl A, Chan KL, Burr ML, Gearing LJ, Willson T, Liu J, Choi J, Yang Y, Bilardi RA, Falk H, Nguyen N, Stupple PA, Peat TS, Zhang M, de Silva M, Carrasco-Pozo C, Avery VM, Khoo PS, Dolezal O, Dennis ML, Nuttall S, Surjadi R, Newman J, Ren B, Leaver DJ, Sun Y, Baell JB, Dovey O, Vassiliou GS, Grebien F, Dawson SJ, Street IP, Monahan BJ, Burns CJ, Choudhary C, Blewitt ME, Voss AK, Thomas T, Dawson MA Nature. 2019 Dec 11. pii: 10.1038/s41586-019-1835-6. doi:, 10.1038/s41586-019-1835-6. PMID:31827282<ref>PMID:31827282</ref>

-	~~Description: HBO1 is required for~~ the ~~maintenance~~ of ~~leukaemia stem cells~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Street, I]]~~	+	<div class="pdbe-citations 6maj" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Peat, T.S~~]]	+	== References ==
-	[[Category: ~~Monahan, B~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Histone acetyltransferase]]
		+	[[Category: Large Structures]]
	[[Category: Dawson, M]]		[[Category: Dawson, M]]
		+	[[Category: Monahan, B]]
		+	[[Category: Peat, T S]]
	[[Category: Ren, B]]		[[Category: Ren, B]]
		+	[[Category: Street, I]]
		+	[[Category: Antitumor protein]]
		+	[[Category: Antitumor protein-inhibitor complex]]
		+	[[Category: Cancer inhibitor]]
		+	[[Category: Myst domain]]

OCA at 14:59, 14 August 2019

OCA — Wed, 14 Aug 2019 14:59:03 GMT

←Older revision		Revision as of 14:59, 14 August 2019
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6maj is ON HOLD until ~~Paper Publication~~	+	The entry 6maj is ON HOLD until Dec 28 2020

	Authors: Ren, B., Peat, T.S., Monahan, B., Dawson, M., Street, I.		Authors: Ren, B., Peat, T.S., Monahan, B., Dawson, M., Street, I.

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

OCA — Wed, 05 Sep 2018 08:53:14 GMT

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

←Older revision

Revision as of 08:53, 5 September 2018

OCA: New page: '''Unreleased structure''' The entry 6maj is ON HOLD until Paper Publication Authors: Ren, B., Peat, T.S., Monahan, B., Dawson, M., Street, I. Description: HBO1 is required for the mai...

OCA — Wed, 05 Sep 2018 08:53:13 GMT

New page: '''Unreleased structure''' The entry 6maj is ON HOLD until Paper Publication Authors: Ren, B., Peat, T.S., Monahan, B., Dawson, M., Street, I. Description: HBO1 is required for the mai...

New page

'''Unreleased structure'''

The entry 6maj is ON HOLD until Paper Publication

Authors: Ren, B., Peat, T.S., Monahan, B., Dawson, M., Street, I.

Description: HBO1 is required for the maintenance of leukaemia stem cells
[[Category: Unreleased Structures]]
[[Category: Street, I]]
[[Category: Peat, T.S]]
[[Category: Monahan, B]]
[[Category: Dawson, M]]
[[Category: Ren, B]]