4PZT

Crystal structure of p300 histone acetyltransferase domain in complex with an inhibitor, Acetonyl-Coenzyme A

4PZT の概要

• エントリーDOI: 10.2210/pdb4pzt/pdb
• 関連するPDBエントリー: 4PZR 4PZS
• 分子名称: Histone acetyltransferase p300, [(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-4-HYDROXY-3-(PHOSPHONOOXY)TETRAHYDROFURAN-2-YL]METHYL (3R)-3-HYDROXY-2,2-DIMETHYL-4-OXO-4-{[3-OXO-3-({2-[(2-OXOPROPYL)THIO]ETHYL}AMINO)PROPYL]AMINO}BUTYL DIHYDROGEN DIPHOSPHATE, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q09472
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44759.68

構造登録者

Maksimoska, J.,Marmorstein, R. (登録日: 2014-03-31, 公開日: 2014-06-11, 最終更新日: 2023-09-20)

主引用文献

Maksimoska, J.,Segura-Pena, D.,Cole, P.A.,Marmorstein, R.
Structure of the p300 Histone Acetyltransferase Bound to Acetyl-Coenzyme A and Its Analogues.
Biochemistry, 53:3415-3422, 2014

PubMed Abstract: The p300 and CBP transcriptional coactivator paralogs (p300/CBP) regulate a variety of different cellular pathways, in part, by acetylating histones and more than 70 non-histone protein substrates. Mutation, chromosomal translocation, or other aberrant activities of p300/CBP are linked to many different diseases, including cancer. Because of its pleiotropic biological roles and connection to disease, it is important to understand the mechanism of acetyl transfer by p300/CBP, in part so that inhibitors can be more rationally developed. Toward this goal, a structure of p300 bound to a Lys-CoA bisubstrate HAT inhibitor has been previously elucidated, and the enzyme's catalytic mechanism has been investigated. Nonetheless, many questions underlying p300/CBP structure and mechanism remain. Here, we report a structural characterization of different reaction states in the p300 activity cycle. We present the structures of p300 in complex with an acetyl-CoA substrate, a CoA product, and an acetonyl-CoA inhibitor. A comparison of these structures with the previously reported p300/Lys-CoA complex demonstrates that the conformation of the enzyme active site depends on the interaction of the enzyme with the cofactor, and is not apparently influenced by protein substrate lysine binding. The p300/CoA crystals also contain two poly(ethylene glycol) moieties bound proximal to the cofactor binding site, implicating the path of protein substrate association. The structure of the p300/acetonyl-CoA complex explains the inhibitory and tight binding properties of the acetonyl-CoA toward p300. Together, these studies provide new insights into the molecular basis of acetylation by p300 and have implications for the rational development of new small molecule p300 inhibitors.

PubMed: 24819397
DOI: 10.1021/bi500380f

実験手法

X-RAY DIFFRACTION (2.8 Å)