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Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8925-30. doi: 10.1073/pnas.1114117109. Epub 2012 May 21.

Structural basis for substrate specificity and catalysis of human histone acetyltransferase 1.

Author information

  • 1Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G 1L7.

Erratum in

  • Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18339.

Abstract

Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4. Here we report a 1.9-Å resolution crystal structure of human histone acetyltransferase 1 in complex with acetyl coenzyme A and histone H4 peptide. The crystal structure reveals that the cofactor and the side chain of lysine 12 of histone H4 peptide are placed in the canyon between the central and C-terminal domains. Histone H4 peptide adopts a well-defined conformation and establishes an extensive set of interactions with the enzyme including invariant residues Glu64 and Trp199, which together govern substrate-binding specificity of histone acetyltransferase 1. Our structure-guided enzyme kinetic study further demonstrates a cumulative effect of the active-site residues Glu187, Glu276, and Asp277 on deprotonation of the ε-amino group of reactive Lys12 for direct attack of the acetyl group of the cofactor.

PMID:
22615379
[PubMed - indexed for MEDLINE]
PMCID:
PMC3384170
Free PMC Article

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