The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p

• Published in: The EMBO journal Vol. 19; no. 22; pp. 6141 - 6149
• Main Authors: Owen, David J., Ornaghi, Prisca, Yang, Ji-Chun, Lowe, Nicholas, Evans, Philip R., Ballario, Paola, Neuhaus, David, Filetici, Patrizia, Travers, Andrew A.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15-11-2000; Blackwell Publishing Ltd; Oxford University Press
• Subjects: acetylated histone H4; Acetylation; Acetyltransferases - chemistry; Acetyltransferases - genetics; Acetyltransferases - metabolism; Amino Acid Sequence; Amino acids; Binding Sites; bromodomain structure; Carbonyl compounds; Crystallization; Crystallography, X-Ray; DNA-Binding Proteins; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gcn5 protein; histone acetyltransferase Gcn5p; Histone Acetyltransferases; Histones - chemistry; Histones - metabolism; Lysine - chemistry; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Nitrogen; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides; Protein Conformation; Protein Kinases - chemistry; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Structure, Tertiary; recognition; Residues; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/19.22.6141

The bromodomain is an ∼110 amino acid module found in histone acetyltransferases and the ATPase component of certain nucleosome remodelling complexes. We report the crystal structure at 1.9 Å resolution of the Saccharomyces cerevisiae Gcn5p bromodomain complexed with a peptide corresponding to residues 15–29 of histone H4 acetylated at the ζ‐N of lysine 16. We show that this bromodomain preferentially binds to peptides containing an N‐acetyl lysine residue. Only residues 16–19 of the acetylated peptide interact with the bromodomain. The primary interaction is the N‐acetyl lysine binding in a cleft with the specificity provided by the interaction of the amide nitrogen of a conserved asparagine with the oxygen of the acetyl carbonyl group. A network of water‐mediated H‐bonds with protein main chain carbonyl groups at the base of the cleft contributes to the binding. Additional side chain binding occurs on a shallow depression that is hydrophobic at one end and can accommodate charge interactions at the other. These findings suggest that the Gcn5p bromodomain may discriminate between different acetylated lysine residues depending on the context in which they are displayed.