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

Nature. 1999 Sep 2;401(6748):93-8. doi: 10.1038/43487.


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 epsilon-amino group of specific lysine residues within the aminoterminal tails of core histones to facilitate access to DNA by transcriptional activators. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / chemistry*
  • Acetyltransferases / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Coenzyme A / chemistry*
  • Coenzyme A / metabolism
  • Crystallography, X-Ray
  • Escherichia coli
  • Histone Acetyltransferases
  • Histones / chemistry*
  • Histones / metabolism
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Tetrahymena / enzymology*


  • Histones
  • Macromolecular Substances
  • Acetyltransferases
  • Histone Acetyltransferases
  • tGCN5 histone acetyltransferase
  • Coenzyme A

Associated data

  • PDB/1QSN
  • PDB/1QSR
  • PDB/1QST