6PX9

Crystal structure of procaspase-8 in complex with covalent small molecule inhibitor 63-R

6PX9 の概要

• エントリーDOI: 10.2210/pdb6px9/pdb
• 分子名称: Caspase-8, N-{(3R)-1-[4-(morpholin-4-yl)benzene-1-carbonyl]piperidin-3-yl}-N-phenylacetamide (3 entities in total)
• 機能のキーワード: zymogen, procaspase, covalent inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 187585.13

構造登録者

Xu, J.H.,Wolan, D.W. (登録日: 2019-07-25, 公開日: 2020-01-29, 最終更新日: 2024-11-06)

主引用文献

Xu, J.H.,Eberhardt, J.,Hill-Payne, B.,Gonzalez-Paez, G.E.,Castellon, J.O.,Cravatt, B.F.,Forli, S.,Wolan, D.W.,Backus, K.M.
Integrative X-ray Structure and Molecular Modeling for the Rationalization of Procaspase-8 Inhibitor Potency and Selectivity.
Acs Chem.Biol., 15:575-586, 2020

PubMed Abstract: Caspases are a critical class of proteases involved in regulating programmed cell death and other biological processes. Selective inhibitors of individual caspases, however, are lacking, due in large part to the high structural similarity found in the active sites of these enzymes. We recently discovered a small-molecule inhibitor, , that covalently binds the zymogen, or inactive precursor (pro-form), of caspase-8, but not other caspases, pointing to an untapped potential of procaspases as targets for chemical probes. Realizing this goal would benefit from a structural understanding of how small molecules bind to and inhibit caspase zymogens. There have, however, been very few reported procaspase structures. Here, we employ X-ray crystallography to elucidate a procaspase-8 crystal structure in complex with , which reveals large conformational changes in active-site loops that accommodate the intramolecular cleavage events required for protease activation. Combining these structural insights with molecular modeling and mutagenesis-based biochemical assays, we elucidate key interactions required for inhibition of procaspase-8. Our findings inform the mechanism of caspase activation and its disruption by small molecules and, more generally, have implications for the development of small molecule inhibitors and/or activators that target alternative (e.g., inactive precursor) protein states to ultimately expand the druggable proteome.

PubMed: 31927936
DOI: 10.1021/acschembio.0c00019

実験手法

X-RAY DIFFRACTION (2.88 Å)