5JIY

Structure of G9a SET-domain with Histone H3K9norLeucine mutant peptide and bound S-adenosylmethionine

Summary for 5JIY

• Entry DOI: 10.2210/pdb5jiy/pdb
• Related: 5JHN 5JIN 5JJ0
• Descriptor: Histone-lysine N-methyltransferase EHMT2, Histone H3.1 mutant peptide with H3K9nor-leucine, ZINC ION, ... (5 entities in total)
• Functional Keywords: set-domain, histone methyl transferase, histone peptide, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q96KQ7
• Total number of polymer chains: 4
• Total formula weight: 66886.45

Authors

Jayaram, H.,Bellon, S.F.,Poy, F. (deposition date: 2016-04-22, release date: 2016-09-14, Last modification date: 2024-10-23)

Primary citation

Jayaram, H.,Hoelper, D.,Jain, S.U.,Cantone, N.,Lundgren, S.M.,Poy, F.,Allis, C.D.,Cummings, R.,Bellon, S.,Lewis, P.W.
S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3.
Proc.Natl.Acad.Sci.USA, 113:6182-6187, 2016

PubMed Abstract: Lysine to methionine (K-to-M) mutations in genes encoding histone H3 are thought to drive a subset of pediatric brain and bone cancers. These high-frequency K-to-M mutations occur at sites of methylation on histone H3, and tumors containing the mutant histones exhibit a global loss of specific histone methylation marks. Previous studies showed that K-to-M mutant histones, also known as oncohistones, are potent orthosteric inhibitors of specific Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain methyltransferases. However, the biochemical and biophysical details of the interaction between K-to-M mutant histones and the respective SET domain methyltransferases are currently unknown. Here, we use the histone H3K9-directed methyltransferase G9a as a model to explore the mechanism of inhibition by K-to-M oncohistones. X-ray cocrystal structures revealed that the K9M residue of histone H3 occupies the active site cavity of G9a, and kinetic analysis indicates competitive inhibition of G9a by histone H3K9M. Additionally, we find that the cofactor S-adenosyl methionine (SAM) is necessary for stable interaction between G9a and H3K9M histone. Consistent with the formation of a ternary complex, we find that the inhibitory peptide is uncompetitive with regard to SAM. These data and others indicate that K-to-M oncohistones promote global loss of specific lysine methylation through sequestration and inhibition of SAM-bound SET domain methyltransferases.

PubMed: 27185940
DOI: 10.1073/pnas.1605523113

Experimental method

X-RAY DIFFRACTION (1.48 Å)