3ARY: Crystal Structure Analysis Of Chitinase A From Vibrio Harveyi With Novel Inhibitors - Complex Structure With 2-(imidazolin-2-yl)-5- Isothiocyanatobenzofuran

Citation:
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.
PDB ID: 3ARYDownload
MMDB ID: 89959
PDB Deposition Date: 2010/12/9
Updated in MMDB: 2011/05
Experimental Method:
x-ray diffraction
Resolution: 1.35  Å
Source Organism:
Similar Structures:
Biological Unit for 3ARY: monomeric; determined by author and by software (PISA)
Molecular Components in 3ARY
Label Count Molecule
Protein (1 molecule)
1
Chitinase a
Molecule annotation
Chemicals (5 molecules)
1
2
2
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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