Title

The structural basis of protein acetylation by the p300/CBP transcriptional coactivator

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

2-14-2008

Document Type

Article

Medical Subject Headings

Acetylation; Amino Acid Sequence; Catalysis; Crystallography, X-Ray; Dimerization; Histone Acetyltransferases; synthesis; Kinetics; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; Structure-Activity Relationship; p300-CBP Transcription Factors; synthesis

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

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.

Rights and Permissions

Citation: Nature. 2008 Feb 14;451(7180):846-50. doi: 10.1038/nature06546. Link to article on publisher's site

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed