5vsf

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Structure of human GLP SET-domain (EHMT1) in complex with inhibitor 17

Structural highlights

5vsf is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:9HG, DIO, GOL, SAM, ZN
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

Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors.,Xiong Y, Li F, Babault N, Wu H, Dong A, Zeng H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J Bioorg Med Chem. 2017 Aug 15;25(16):4414-4423. doi: 10.1016/j.bmc.2017.06.021., Epub 2017 Jun 19. PMID:28662962[3]

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

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Xiong Y, Li F, Babault N, Wu H, Dong A, Zeng H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J. Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorg Med Chem. 2017 Aug 15;25(16):4414-4423. doi: 10.1016/j.bmc.2017.06.021., Epub 2017 Jun 19. PMID:28662962 doi:http://dx.doi.org/10.1016/j.bmc.2017.06.021

Contents


PDB ID 5vsf

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OCA

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