Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294
Xing Zhang,John R. Horton,Anup K. Upadhyay,Astrid Spannhoff,Jin Liu,James P. Snyder,Mark T. Bedford,Xiaodong Cheng +7 more
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TLDR
The crystal structure of the catalytic SET domain of GLP in complex with BIX-01294 and S-adenosyl-L-homocysteine is presented and it is shown that the inhibitor resembles the bound conformation of histone H3 Lys4 to Arg8, and is positioned in place by residues specific for G9a and GLP through specific interactions.Abstract:
Histone lysine methylation is an important epigenetic mark that regulates gene expression and chromatin organization. G9a and G9a-like protein (GLP) are euchromatin-associated methyltransferases that repress transcription by methylating histone H3 Lys9. BIX-01294 was originally identified as a G9a inhibitor during a chemical library screen of small molecules and has previously been used in the generation of induced pluripotent stem cells. Here we present the crystal structure of the catalytic SET domain of GLP in complex with BIX-01294 and S-adenosyl-L-homocysteine. The inhibitor is bound in the substrate peptide groove at the location where the histone H3 residues N-terminal to the target lysine lie in the previously solved structure of the complex with histone peptide. The inhibitor resembles the bound conformation of histone H3 Lys4 to Arg8, and is positioned in place by residues specific for G9a and GLP through specific interactions.read more
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Epigenetic protein families: a new frontier for drug discovery
Cheryl H. Arrowsmith,C. Bountra,Paul V. Fish,Kevin Lee,Kevin Lee,Matthieu Schapira,Matthieu Schapira +6 more
TL;DR: The key protein families that mediate epigenetic signalling through the acetylation and methylation of histones are reviewed, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones.
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Epigenetic modifications as therapeutic targets
TL;DR: The presence of multiple epigenetic aberrations within malignant tissue and the abilities of cells to develop resistance suggest that epigenetic therapies are most beneficial when combined with other anticancer strategies, such as signal transduction inhibitors or cytotoxic treatments.
Journal ArticleDOI
Essential Role of the Histone Methyltransferase G9a in Cocaine-induced Plasticity
Ian Maze,Herbert E. Covington,David M. Dietz,Quincey LaPlant,Quincey LaPlant,William Renthal,Scott J. Russo,Max Mechanic,Ezekiell Mouzon,Rachael L. Neve,Stephen J. Haggarty,Stephen J. Haggarty,Yanhua Ren,Srihari C. Sampath,Yasmin L. Hurd,Paul Greengard,Alexander Tarakhovsky,Anne Schaefer,Eric J. Nestler +18 more
TL;DR: Using conditional mutagenesis and viral-mediated gene transfer, it is found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
Journal ArticleDOI
Microscale thermophoresis quantifies biomolecular interactions under previously challenging conditions
Susanne A. I. Seidel,Patricia M. Dijkman,Wendy A. Lea,Geert van den Bogaart,Moran Jerabek-Willemsen,Ana Lazic,Jeremiah S. Joseph,Prakash Srinivasan,Philipp Baaske,Anton Simeonov,Ilia Katritch,Fernando A. Melo,John E. Ladbury,Gideon Schreiber,Anthony Watts,Dieter Braun,Stefan Duhr +16 more
TL;DR: Flexibility in assay design qualifies MST for analysis of biomolecular interactions in complex experimental settings, which is demonstrated by addressing typically challenging types of binding events from various fields of life science.
Journal ArticleDOI
H3K9 methyltransferase G9a and the related molecule GLP
Yoichi Shinkai,Makoto Tachibana +1 more
TL;DR: The discovery of Suv39h1, the first SET domain-containing histone lysine methyltransferase (HKMT), was reported in 2000, and recently, many important studies have reported that G9a and GLP play critical roles in various biological processes.
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TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.