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Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294

Nature Structural & Molecular Biology volume 16, pages 312–317 (2009)Cite this article

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.

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Figure 1: Effect of BIX-01294.
Figure 2: Structure of the GLP SET–AdoHcy–BIX-01294 complex.
Figure 3: Details of GLP SET–BIX-01294 interactions.

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Acknowledgements

We thank P.R. Thompson and C. Causey for critical comments. The Biochemistry Department of Emory University School of Medicine supported the use of SER-CAT beamlines. This work was supported by grant GM068680 to X.C. from the US National Institutes of Health and the Welch Foundation Grant G-1495 to M.T.B. X.C. is funded by the Georgia Research Alliance.

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Authors and Affiliations

  1. Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Yanqi Chang, Xing Zhang, John R Horton, Anup K Upadhyay & Xiaodong Cheng

  2. Department of Carcinogenesis, M.D. Anderson Cancer Center, University of Texas, 1808 Park Road 1C, Smithville, 78957, Texas, USA

    Astrid Spannhoff & Mark T Bedford

  3. Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, 30322, Georgia, USA

    Jin Liu & James P Snyder

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Correspondence to Xiaodong Cheng.

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Chang, Y., Zhang, X., Horton, J. et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol 16, 312–317 (2009). https://doi.org/10.1038/nsmb.1560

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