3AS0

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

Summary for 3AS0

• Entry DOI: 10.2210/pdb3as0/pdb
• Related: 3ARO 3ARP 3ARQ 3ARR 3ARS 3ART 3ARU 3ARV 3ARW 3ARX 3ARY 3ARZ 3AS1 3AS2 3AS3
• Descriptor: Chitinase A, 13-methyl[1,3]benzodioxolo[5,6-c][1,3]dioxolo[4,5-i]phenanthridin-13-ium, GLYCEROL, ... (4 entities in total)
• Functional Keywords: tim barrel, inhibitor complex, glycosidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Vibrio harveyi
• Total number of polymer chains: 1
• Total formula weight: 64469.37

Authors

Pantoom, S.,Vetter, I.R.,Prinz, H.,Suginta, W. (deposition date: 2010-12-09, release date: 2011-04-20, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)