3FPD

G9a-like protein lysine methyltransferase inhibition by BIX-01294

Summary for 3FPD

• Entry DOI: 10.2210/pdb3fpd/pdb
• Related: 2RFI
• Descriptor: Histone-lysine N-methyltransferase, H3 lysine-9 specific 5, S-ADENOSYL-L-HOMOCYSTEINE, N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine, ... (5 entities in total)
• Functional Keywords: epigenetics, histone lysine methylation, catalytic set domain, inhibition by bix-01294, alternative splicing, ank repeat, chromatin regulator, metal-binding, methyltransferase, nucleus, phosphoprotein, polymorphism, s-adenosyl-l-methionine, transferase, zinc
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9H9B1
• Total number of polymer chains: 2
• Total formula weight: 62738.12

Authors

Chang, Y.,Zhang, X.,Horton, J.R.,Cheng, X. (deposition date: 2009-01-05, release date: 2009-02-17, Last modification date: 2023-09-06)

Primary citation

Chang, Y.,Zhang, X.,Horton, J.R.,Upadhyay, A.K.,Spannhoff, A.,Liu, J.,Snyder, J.P.,Bedford, M.T.,Cheng, X.
Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294.
Nat.Struct.Mol.Biol., 16:312-317, 2009

PubMed 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.

PubMed: 19219047
DOI: 10.1038/nsmb.1560

Experimental method

X-RAY DIFFRACTION (2.4 Å)