6H23

Crystal structure of the hClpP Y118A mutant with an activating small molecule

6H23 の概要

• エントリーDOI: 10.2210/pdb6h23/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, mitochondrial, ~{N}-(1,3-benzodioxol-5-ylmethyl)-5-[(2-chloranyl-4-fluoranyl-phenyl)methyl]-1,3,4-oxadiazole-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: protease, small molecule, 14mer, serine protease, oligomerization, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 357664.49

構造登録者

Kick, L.M.,Sieber, S.A.,Schneider, S. (登録日: 2018-07-13, 公開日: 2018-08-29, 最終更新日: 2024-05-15)

主引用文献

Stahl, M.,Korotkov, V.S.,Balogh, D.,Kick, L.M.,Gersch, M.,Pahl, A.,Kielkowski, P.,Richter, K.,Schneider, S.,Sieber, S.A.
Selective Activation of Human Caseinolytic Protease P (ClpP).
Angew. Chem. Int. Ed. Engl., 57:14602-14607, 2018

PubMed Abstract: Caseinolytic protease P (ClpP) is the proteolytic component of the ClpXP protein degradation complex. Eukaryotic ClpP was recently found to act within the mitochondria-specific unfolded protein response (UPR ). However, its detailed function and dedicated regulation remain largely unexplored. A small molecule (D9) acts as a potent and species-selective activator of human ClpP (hClpP) by mimicking the natural chaperone ClpX. Structure-activity relationship studies highlight the importance of a halogenated benzyl motif within D9 that interacts with a unique aromatic amino acid network in hClpP. Mutational and structural studies suggest that this YYW motif tightly controls hClpP activity and regulates substrate turnover by interaction with cognate ligands. This signature motif is unique to ClpP from higher organisms and does not exist in tested bacterial homologues, allowing a species-selective analysis. Thus, D9 is a versatile tool to analyze mechanistic features of hClpP.

PubMed: 30129683
DOI: 10.1002/anie.201808189

実験手法

X-RAY DIFFRACTION (3.089 Å)