Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide

Jeannie R. Rojas, Raymond C. Trievel, Jianxin Zhou, Yi Mo, Xinmin Li, Shelley L. Berger, C. David Allis and Ronen Marmorstein ()
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Jeannie R. Rojas: The Wistar Institute
Raymond C. Trievel: The Wistar Institute
Jianxin Zhou: University of Rochester
Yi Mo: The Wistar Institute
Xinmin Li: The Wistar Institute
Shelley L. Berger: The Wistar Institute
C. David Allis: University of Rochester
Ronen Marmorstein: The Wistar Institute

Nature, 1999, vol. 401, issue 6748, 93-98

Abstract: Abstract Gene activation is a highly regulated process that requires the coordinated action of proteins to relieve chromatin repression and to promote transcriptional activation. Nuclear histone acetyltransferase (HAT) enzymes provide a mechanistic link between chromatin destabilization and gene activation by acetylating the ε-amino group of specific lysine residues within the amino-terminal tails of core histones to facilitate access to DNA by transcriptional activators1,2. Here we report the high-resolution crystal structure of the HAT domain of Tetrahymena GCN5 (tGCN5) bound with both its physiologically relevant ligands, coenzyme A (CoA) and a histone H3 peptide, and the structures of nascent tGCN5 and a tGCN5/acetyl-CoA complex. Our structural data reveal histone-binding specificity for a random-coil structure containing a G-K-X-P recognition sequence, and show that CoA is essential for reorienting the enzyme for histone binding. Catalysis appears to involve water-mediated proton extraction from the substrate lysine by a glutamic acid general base and a backbone amide that stabilizes the transition-state reaction intermediate. Comparison with related N-acetyltransferases indicates a conserved structural framework for CoA binding and catalysis, and structural variability in regions associated with substrate-specific binding.

Date: 1999
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DOI: 10.1038/43487

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