The structural basis of protein acetylation by the p300/CBP transcriptional coactivator
Thompson, Paul R
Cole, Philip A.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Amino Acid Sequence
Molecular Sequence Data
Protein Structure, Tertiary
p300-CBP Transcription Factors
Enzymes and Coenzymes
MetadataShow full item record
AbstractThe 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.
SourceNature. 2008 Feb 14;451(7180):846-50. doi: 10.1038/nature06546. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/50064
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related ResourcesLink to Article in PubMed