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5jiy

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Revision as of 07:51, 10 June 2020

Structure of G9a SET-domain with Histone H3K9norLeucine mutant peptide and bound S-adenosylmethionine

Structural highlights

5jiy is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Related:	5jin, 5jhn, 5jj0
Gene:	EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[EHMT2_HUMAN] Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactor S-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. These data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.,Jayaram H, Hoelper D, Jain SU, Cantone N, Lundgren SM, Poy F, Allis CD, Cummings R, Bellon S, Lewis PW Proc Natl Acad Sci U S A. 2016 May 31;113(22):6182-7. doi:, 10.1073/pnas.1605523113. Epub 2016 May 16. PMID:27185940^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Milner CM, Campbell RD. The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats. Biochem J. 1993 Mar 15;290 ( Pt 3):811-8. PMID:8457211
↑ Tachibana M, Sugimoto K, Fukushima T, Shinkai Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem. 2001 Jul 6;276(27):25309-17. Epub 2001 Apr 20. PMID:11316813 doi:10.1074/jbc.M101914200
↑ Rathert P, Dhayalan A, Murakami M, Zhang X, Tamas R, Jurkowska R, Komatsu Y, Shinkai Y, Cheng X, Jeltsch A. Protein lysine methyltransferase G9a acts on non-histone targets. Nat Chem Biol. 2008 Jun;4(6):344-6. doi: 10.1038/nchembio.88. Epub 2008 Apr 27. PMID:18438403 doi:10.1038/nchembio.88
↑ Huang J, Dorsey J, Chuikov S, Zhang X, Jenuwein T, Reinberg D, Berger SL. G9A and GLP methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010 Jan 29. PMID:20118233 doi:M109.062588
↑ Yu Y, Song C, Zhang Q, DiMaggio PA, Garcia BA, York A, Carey MF, Grunstein M. Histone H3 lysine 56 methylation regulates DNA replication through its interaction with PCNA. Mol Cell. 2012 Apr 13;46(1):7-17. doi: 10.1016/j.molcel.2012.01.019. Epub 2012, Mar 1. PMID:22387026 doi:10.1016/j.molcel.2012.01.019
↑ Jayaram H, Hoelper D, Jain SU, Cantone N, Lundgren SM, Poy F, Allis CD, Cummings R, Bellon S, Lewis PW. S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3. Proc Natl Acad Sci U S A. 2016 May 31;113(22):6182-7. doi:, 10.1073/pnas.1605523113. Epub 2016 May 16. PMID:27185940 doi:http://dx.doi.org/10.1073/pnas.1605523113

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5jiy"

@@ Line 1: / Line 1: @@
 ==Structure of G9a SET-domain with Histone H3K9norLeucine mutant peptide and bound S-adenosylmethionine==
-<StructureSection load='5jiy' size='340' side='right' caption='[[5jiy]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
+<StructureSection load='5jiy' size='340' side='right'caption='[[5jiy]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5jiy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JIY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JIY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5jiy]] 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=5JIY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5JIY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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=NLE:NORLEUCINE'>NLE</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jin|5jin]], [[5jhn|5jhn]], [[5jj0|5jj0]]</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=5jiy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jiy OCA], [http://pdbe.org/5jiy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jiy RCSB], [http://www.ebi.ac.uk/pdbsum/5jiy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jiy ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 ([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=5jiy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jiy OCA], [http://pdbe.org/5jiy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jiy RCSB], [http://www.ebi.ac.uk/pdbsum/5jiy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jiy ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5jiy" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Bellon, S F]]
 [[Category: Jayaram, H]]

5jiy

From Proteopedia

Revision as of 07:51, 10 June 2020

Structure of G9a SET-domain with Histone H3K9norLeucine mutant peptide and bound S-adenosylmethionine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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