4FXO

Zinc-mediated allosteric inhibiton of caspase-6

4FXO の概要

• エントリーDOI: 10.2210/pdb4fxo/pdb
• 関連するPDBエントリー: 2WDP 3K7E 3NKF 3OD5 3S8E
• 分子名称: Caspase-6, ZINC ION (3 entities in total)
• 機能のキーワード: heterotetramer, hydrolase, cytosol, apoptosis
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P55212
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 137013.18

構造登録者

Velazquez-Delgado, E.M.,Hardy, J.A. (登録日: 2012-07-03, 公開日: 2012-08-22, 最終更新日: 2023-09-13)

主引用文献

Velazquez-Delgado, E.M.,Hardy, J.A.
Zinc-mediated Allosteric Inhibition of Caspase-6.
J.Biol.Chem., 287:36000-36011, 2012

PubMed Abstract: Zinc and caspase-6 have independently been implicated in several neurodegenerative disorders. Depletion of zinc intracellularly leads to apoptosis by an unknown mechanism. Zinc inhibits cysteine proteases, including the apoptotic caspases, leading to the hypothesis that zinc-mediated inhibition of caspase-6 might contribute to its regulation in a neurodegenerative context. Using inductively coupled plasma optical emission spectroscopy, we observed that caspase-6 binds one zinc per monomer, under the same conditions where the zinc leads to complete loss of enzymatic activity. To understand the molecular details of zinc binding and inhibition, we performed an anomalous diffraction experiment above the zinc edge. The anomalous difference maps showed strong 5σ peaks, indicating the presence of one zinc/monomer bound at an exosite distal from the active site. Zinc was not observed bound to the active site. The zinc in the exosite was liganded by Lys-36, Glu-244, and His-287 with a water molecule serving as the fourth ligand, forming a distorted tetrahedral ligation sphere. This exosite appears to be unique to caspase-6, as the residues involved in zinc binding were not conserved across the caspase family. Our data suggest that binding of zinc at the exosite is the primary route of inhibition, potentially locking caspase-6 into the inactive helical conformation.

PubMed: 22891250
DOI: 10.1074/jbc.M112.397752

実験手法

X-RAY DIFFRACTION (2.85 Å)