6PF1

Crystal structure of the p300 acetyltransferase domain with allosteric inhibitor CPI-090 and CoA

6PF1 の概要

• エントリーDOI: 10.2210/pdb6pf1/pdb
• 分子名称: Histone acetyltransferase p300, COENZYME A, 3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-methyl-1H-indole, ... (4 entities in total)
• 機能のキーワード: ep300, p300 acetyltransferase, chromatin modification, epigenetics, inhibitor, allosteric, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80325.55

構造登録者

Gardberg, A.S. (登録日: 2019-06-21, 公開日: 2019-10-23, 最終更新日: 2024-03-13)

主引用文献

Gardberg, A.S.,Huhn, A.J.,Cummings, R.,Bommi-Reddy, A.,Poy, F.,Setser, J.,Vivat, V.,Brucelle, F.,Wilson, J.
Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT.
Struct Dyn., 6:054702-054702, 2019

PubMed Abstract: Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme.

PubMed: 31649965
DOI: 10.1063/1.5119336

実験手法

X-RAY DIFFRACTION (2.32 Å)