PDBsum entry 3as3

Hydrolase/hydrolase inhibitor

PDB id: 3as3

Contents

Protein chain

567 a.a.

Ligands

I5I ×2

GOL

Waters ×224

References listed in PDB file

Key reference

• Title: Potent family-18 chitinase inhibitors: X-Ray structures, Affinities, And binding mechanisms.
• Authors: S.Pantoom, I.R.Vetter, H.Prinz, W.Suginta.
• Ref.: J Biol Chem, 2011, 286, 24312-24323.
• PubMed id: 21531720

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.

Secondary reference #1

• Title: Crystal structures of vibrio harveyi chitinase a complexed with chitooligosaccharides: implications for the catalytic mechanism.
• Authors: C.Songsiriritthigul, S.Pantoom, A.H.Aguda, R.C.Robinson, W.Suginta.
• Ref.: J Struct Biol, 2008, 162, 491-499. [DOI no: 10.1016/j.jsb.2008.03.008]
• PubMed id: 18467126