6h8p - Revision history

OCA at 07:56, 12 September 2018

OCA — Wed, 12 Sep 2018 07:56:56 GMT

←Older revision		Revision as of 07:56, 12 September 2018
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	<StructureSection load='6h8p' size='340' side='right' caption='[[6h8p]], [[Resolution\|resolution]] 1.98Å' scene=''>		<StructureSection load='6h8p' size='340' side='right' caption='[[6h8p]], [[Resolution\|resolution]] 1.98Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6h8p]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H8P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6h8p]] is a 4 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=6H8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H8P 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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</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=M3L:N-TRIMETHYLLYSINE'>M3L</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=M3L:N-TRIMETHYLLYSINE'>M3L</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">KDM4A, JHDM3A, JMJD2, JMJD2A, KIAA0677 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6h8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h8p OCA], [http://pdbe.org/6h8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h8p RCSB], [http://www.ebi.ac.uk/pdbsum/6h8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h8p 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=6h8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h8p OCA], [http://pdbe.org/6h8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h8p RCSB], [http://www.ebi.ac.uk/pdbsum/6h8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h8p ProSAT]</span></td></tr>
	</table>		</table>
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	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	~~Post~~-~~translational histone modification has a fundamental role in chromatin biology and~~ is ~~proposed to constitute a '~~histone ~~code' in epigenetic regulation~~. ~~Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation~~, ~~X-chromosome inactivation, genome imprinting, DNA repair~~ and ~~transcriptional regulation. The discovery of lysyl demethylases using flavin~~ (~~amine oxidases~~) ~~or Fe~~(II) ~~and 2~~-~~oxoglutarate as cofactors~~ (~~2OG oxygenases~~) ~~has changed the view of methylation as a stable epigenetic marker~~. ~~However, little~~ is ~~known about how the demethylases are selective~~ for ~~particular lysyl~~-~~containing sequences in specific methylation states, a key to understanding their functions~~. ~~Here we reveal how human JMJD2A (jumonji domain containing 2A), which~~ is ~~selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (~~H3K9me3~~/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9~~. ~~We report structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form~~ of ~~H3K36~~. ~~The structures~~ reveal a ~~lysyl-~~binding ~~pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site~~. ~~We propose a mechanism for achieving methylation state selectivity involving~~ the ~~orientation~~ of the ~~substrate methyl groups towards a ferryl intermediate. The~~ results suggest ~~distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect~~ the ~~complexity of reversible histone methylation~~ and ~~its role~~ in ~~chromatin biology~~.	+	N-Methylation of lysyl residues is widely observed on histone proteins. Using isolated enzymes, we report mechanistic and structural studies on histone lysine demethylase (KDM)-catalysed demethylation of N(epsilon) -methylated lysine 26 on histone 1 isotype 4 (H1.4). The results reveal that methylated H1.4K26 is a substrate for all members of the KDM4 subfamily and that KDM4A-catalysed demethylation of H1.4K26me3 peptide is similarly efficient to that of H3K9me3. Crystallographic studies of an H1.4K26me3:KDM4A complex reveal a conserved binding geometry to that of H3K9me3. In light of the high activity of the KDM4s on this mark, our results suggest JmjC KDM-catalysed demethylation of H1.4K26 may be as prevalent as demethylation on the H3 tail and warrants further investigation in cells. This article is protected by copyright. All rights reserved.

-	~~Crystal structures~~ of ~~histone demethylase JMJD2A reveal basis for substrate specificity~~.,~~Ng SS~~, ~~Kavanagh KL~~, ~~McDonough MA~~, ~~Butler D~~, ~~Pilka ES, Lienard BM, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer~~ J, ~~Scheinost JC~~, ~~Borowski T, Sundstrom M~~, Schofield CJ~~, Oppermann U Nature~~. ~~2007 Jul 5;448(7149)~~:87-91. ~~Epub 2007 Jun 24~~. PMID:~~17589501~~<ref>PMID:~~17589501~~</ref>	+	Mechanistic and Structural Studies of KDM-Catalysed Demethylation of Histone 1 Isotype 4 at Lysine 26.,Walport LJ, Hopkinson RJ, Chowdhury R, Zhang Y, Bonnici J, Schiller R, Kawamura A, Schofield CJ FEBS Lett. 2018 Aug 29. doi: 10.1002/1873-3468.13231. PMID:30156264<ref>PMID:30156264</ref>

	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Chowdhury, R]]		[[Category: Chowdhury, R]]
	[[Category: Schofield, C J]]		[[Category: Schofield, C J]]

OCA at 16:25, 15 August 2018

OCA — Wed, 15 Aug 2018 16:25:49 GMT

←Older revision		Revision as of 16:25, 15 August 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6h8p is ~~ON HOLD~~	+	==JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)==
		+	<StructureSection load='6h8p' size='340' side='right' caption='[[6h8p]], [[Resolution\|resolution]] 1.98Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6h8p]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H8P 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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=OGA:N-OXALYLGLYCINE'>OGA</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=M3L:N-TRIMETHYLLYSINE'>M3L</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=6h8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h8p OCA], [http://pdbe.org/6h8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h8p RCSB], [http://www.ebi.ac.uk/pdbsum/6h8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h8p ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/KDM4A_HUMAN KDM4A_HUMAN]] Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref> Isoform 2: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.<ref>PMID:16024779</ref> <ref>PMID:16603238</ref> <ref>PMID:21694756</ref> [[http://www.uniprot.org/uniprot/H14_HUMAN H14_HUMAN]] Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a 'histone code' in epigenetic regulation. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochromatin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation. The discovery of lysyl demethylases using flavin (amine oxidases) or Fe(II) and 2-oxoglutarate as cofactors (2OG oxygenases) has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.

-	~~Authors: Chowdhury, R~~., ~~Walport~~, L.J., Schofield, C.J.	+	Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity.,Ng SS, Kavanagh KL, McDonough MA, Butler D, Pilka ES, Lienard BM, Bray JE, Savitsky P, Gileadi O, von Delft F, Rose NR, Offer J, Scheinost JC, Borowski T, Sundstrom M, Schofield CJ, Oppermann U Nature. 2007 Jul 5;448(7149):87-91. Epub 2007 Jun 24. PMID:17589501<ref>PMID:17589501</ref>

-	~~Description: JMJD2A~~/ ~~KDM4A COMPLEXED WITH NI(II)~~, ~~NOG AND Histone H1~~.~~4(18~~-~~32)K26me3 peptide (15~~-~~mer)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
		+	<div class="pdbe-citations 6h8p" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Chowdhury, R]]		[[Category: Chowdhury, R]]
-	[[Category: Schofield, C.J]]	+	[[Category: Schofield, C J]]
-	[[Category: Walport, L.J]]	+	[[Category: Walport, L J]]
		+	[[Category: 2-oxoglutarate]]
		+	[[Category: Chromatin regulator]]
		+	[[Category: Demethylase]]
		+	[[Category: Dioxygenase]]
		+	[[Category: Double-stranded beta helix]]
		+	[[Category: Dsbh]]
		+	[[Category: Epigenetic and transcription regulation]]
		+	[[Category: Facial triad]]
		+	[[Category: Histone]]
		+	[[Category: Hydroxylation]]
		+	[[Category: Iron]]
		+	[[Category: Jmjc domain]]
		+	[[Category: Jmjd2a]]
		+	[[Category: Kdm4a]]
		+	[[Category: Metal binding protein]]
		+	[[Category: Non-heme]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Oxygenase]]

OCA: Protected "6h8p" [edit=sysop:move=sysop]

OCA — Thu, 09 Aug 2018 20:10:41 GMT

Protected "6h8p" [edit=sysop:move=sysop]

←Older revision

Revision as of 20:10, 9 August 2018

OCA: New page: '''Unreleased structure''' The entry 6h8p is ON HOLD Authors: Chowdhury, R., Walport, L.J., Schofield, C.J. Description: JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32...

OCA — Thu, 09 Aug 2018 20:10:40 GMT

New page: '''Unreleased structure''' The entry 6h8p is ON HOLD Authors: Chowdhury, R., Walport, L.J., Schofield, C.J. Description: JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32...

New page

'''Unreleased structure'''

The entry 6h8p is ON HOLD

Authors: Chowdhury, R., Walport, L.J., Schofield, C.J.

Description: JMJD2A/ KDM4A COMPLEXED WITH NI(II), NOG AND Histone H1.4(18-32)K26me3 peptide (15-mer)
[[Category: Unreleased Structures]]
[[Category: Chowdhury, R]]
[[Category: Schofield, C.J]]
[[Category: Walport, L.J]]