3BIY

Crystal structure of p300 histone acetyltransferase domain in complex with a bisubstrate inhibitor, Lys-CoA

Summary for 3BIY

• Entry DOI: 10.2210/pdb3biy/pdb
• Descriptor: Histone acetyltransferase p300, BROMIDE ION, [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydrofuran-2-yl]methyl (3R,20R)-20-carbamoyl-3-hydroxy-2,2-dimethyl-4,8,14,22-tetraoxo-12-thia-5,9,15,21-tetraazatricos-1-yl dihydrogen diphosphate, ... (4 entities in total)
• Functional Keywords: p300 hat, bisubstrate inhibitor, protein-inhibitor complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q09472
• Total number of polymer chains: 1
• Total formula weight: 45370.24

Authors

Liu, X.,Wang, L.,Zhao, K.,Thompson, P.R.,Hwang, Y.,Marmorstein, R.,Cole, P.A. (deposition date: 2007-12-02, release date: 2008-02-12, Last modification date: 2024-02-21)

Primary citation

Liu, X.,Wang, L.,Zhao, K.,Thompson, P.R.,Hwang, Y.,Marmorstein, R.,Cole, P.A.
The structural basis of protein acetylation by the p300/CBP transcriptional coactivator
Nature, 451:846-850, 2008

PubMed 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.

PubMed: 18273021
DOI: 10.1038/nature06546

Experimental method

X-RAY DIFFRACTION (1.7 Å)