2brp

From Proteopedia

Revision as of 15:41, 5 November 2007

CRYSTAL STRUCTURE OF S.PNEUMONIAE HYALURONATE LYASE IN COMPLEX WITH W249B

Overview

The bacterial hyaluronan lyases (Hyals) that degrade hyaluronan, an, important component of the extracellular matrix, are involved in microbial, spread. Inhibitors of these enzymes are essential in investigation of the, role of hyaluronan and Hyal in bacterial infections and constitute a new, class of antibiotics against Hyal-producing bacteria. Recently, we, identified 1,3-diacetylbenzimidazole-2-thione and related molecules as, inhibitors of streptococcal Hyal. One of such compounds, 1-decyl-2-(4-sulfamoyloxyphenyl)-1-indol-6-yl sulfamate, was, co-crystallized in a complex with Streptococcus pneumoniae Hyal and its, structure elucidated. The resultant X-ray structure demonstrates that this, inhibitor fits in the enzymatic active site via interactions resembling, the binding mode of the natural hyaluronan substrate. X-ray structural, analysis also indicates binding interactions with the catalytic residues, and those of a catalytically essential hydrophobic patch. An IC50 value of, 11 microM for Hyal from Streptococcus agalactiae (strain 4755) qualifies, this phenylindole compound as one of the most potent Hyal inhibitors known, to date. The structural data suggested a similar binding mode for, N-(3-phenylpropionyl)-benzoxazole-2-thione. This new compound's inhibitory, properties were confirmed resulting in discovery of yet another Hyal, inhibitor (IC50 of 15 microM). These benzoxazole-2-thiones constitute a, new class of inhibitors of bacterial Hyals and are well suited for further, optimization of their selectivity, potency, and pharmacokinetic, properties.

About this Structure

2BRP is a Single protein structure of sequence from Streptococcus pneumoniae with XLS, SO4 and SIE as ligands. Active as Hyaluronate lyase, with EC number 4.2.2.1 Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Design of new benzoxazole-2-thione-derived inhibitors of Streptococcus pneumoniae hyaluronan lyase: structure of a complex with a 2-phenylindole., Rigden DJ, Botzki A, Nukui M, Mewbourne RB, Lamani E, Braun S, von Angerer E, Bernhardt G, Dove S, Buschauer A, Jedrzejas MJ, Glycobiology. 2006 Aug;16(8):757-65. Epub 2006 Apr 25. PMID:16638841

Page seeded by OCA on Mon Nov 5 17:47:02 2007