3AS1

Crystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with chelerythrine

3AS1 の概要

• エントリーDOI: 10.2210/pdb3as1/pdb
• 関連するPDBエントリー: 3ARO 3ARP 3ARQ 3ARR 3ARS 3ART 3ARU 3ARV 3ARW 3ARX 3ARY 3ARZ 3AS0 3AS2 3AS3
• 分子名称: Chitinase A, 1,2-dimethoxy-12-methyl[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: tim barrel, inhibitor complex, glycosidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Vibrio harveyi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 64501.46

構造登録者

Pantoom, S.,Vetter, I.R.,Prinz, H.,Suginta, W. (登録日: 2010-12-09, 公開日: 2011-04-20, 最終更新日: 2024-11-20)

主引用文献

Pantoom, S.,Vetter, I.R.,Prinz, H.,Suginta, W.
Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms
J.Biol.Chem., 286:24312-24323, 2011

PubMed Abstract: Six novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies.

PubMed: 21531720
DOI: 10.1074/jbc.M110.183376

実験手法

X-RAY DIFFRACTION (2 Å)