The Structural Basis of Protein Acetylation by the p300/CBP Transcriptional Coactivator

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Nature

DOI:https://doi.org/10.1038/nature06546· OSTI ID:959502

Liu, X; Wang, L; Zhao, K; Thompson, P; Hwang, Y; Marmorstein, R; Cole, P

The transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/CBP HAT activity contributes to various diseases including cancer. Sequence alignments, enzymology experiments and inhibitor studies on p300/CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/PCAF and MYST HATs. Here we describe a high-resolution X-ray crystal structure of a semi-synthetic heterodimeric p300 HAT domain in complex with a bi-substrate inhibitor, Lys-CoA. This structure shows that p300/CBP is a distant cousin of other structurally characterized HATs, but reveals several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, we propose that p300/CBP uses an unusual 'hit-and-run' (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations can also be readily accounted for by the p300 HAT structure. These studies pave the way for new epigenetic therapies involving modulation of p300/CBP HAT activity.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959502
• Report Number(s): BNL--82488-2009-JA
• Journal Information: Nature, Journal Name: Nature Journal Issue: 7180 Vol. 451
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ACETYLATION
CRYSTAL STRUCTURE
DISEASES
GENES
HISTONES
MODULATION
MUTATIONS
NEOPLASMS
PROTEINS
RESIDUES
SPECIFICITY
SUBSTRATES
TRANSCRIPTION FACTORS
national synchrotron light source