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5tuz

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Revision as of 14:27, 6 November 2017

Structure of human GLP SET-domain (EHMT1) in complex with inhibitor MS0124

Structural highlights

5tuz is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	5tuy
Gene:	EHMT1, EUHMTASE1, GLP, KIAA1876, KMT1D (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[EHMT1_HUMAN] Defects in EHMT1 are the cause of chromosome 9q subtelomeric deletion syndrome (9q- syndrome) [MIM:610253]. Common features seen in these patients are severe mental retardation, hypotonia, brachy(micro)cephaly, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems.

Function

[EHMT1_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 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. During G0 phase, it probably contributes to silencing of MYC- and E2F-responsive genes, suggesting a role in G0/G1 transition in cell cycle. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53.^[1] ^[2]

Publication Abstract from PubMed

G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.,Xiong Y, Li F, Babault N, Dong A, Zeng H, Wu H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J J Med Chem. 2017 Feb 14. doi: 10.1021/acs.jmedchem.6b01645. PMID:28135087^[3]

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

References

↑ Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 2002 May 10;296(5570):1132-6. PMID:12004135 doi:10.1126/science.1069861
↑ 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
↑ Xiong Y, Li F, Babault N, Dong A, Zeng H, Wu H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J. Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase. J Med Chem. 2017 Feb 14. doi: 10.1021/acs.jmedchem.6b01645. PMID:28135087 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01645

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <StructureSection load='5tuz' size='340' side='right' caption='[[5tuz]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tuz]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TUZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TUZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5tuz]] 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=5TUZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TUZ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7L6:6,7-DIMETHOXY-N-(1-METHYLPIPERIDIN-4-YL)-2-(MORPHOLIN-4-YL)QUINAZOLIN-4-AMINE'>7L6</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tuy|5tuy]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EHMT1, EUHMTASE1, GLP, KIAA1876, KMT1D ([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=5tuz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tuz OCA], [http://pdbe.org/5tuz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tuz RCSB], [http://www.ebi.ac.uk/pdbsum/5tuz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tuz ProSAT]</span></td></tr>
 </table>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Babault, N]]
 [[Category: Jin, J]]

5tuz

From Proteopedia

Revision as of 14:27, 6 November 2017

Structure of human GLP SET-domain (EHMT1) in complex with inhibitor MS0124

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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