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A Second, Druggable Binding Site in UDP‐Galactopyranose Mutase from Mycobacterium tuberculosis ?
Author(s) -
Shi Yun,
Colombo Cinzia,
Kuttiyatveetil Jijin R. A.,
Zalatar Nataliya,
van Straaten Karin E.,
Mohan Sankar,
Sanders David A. R.,
Pinto B. Mario
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600469
Subject(s) - druggability , mycobacterium tuberculosis , mutase , tuberculosis , microbiology and biotechnology , binding site , chemistry , computational biology , virology , biology , biochemistry , medicine , enzyme , pathology , gene
UDP‐galactopyranose mutase (UGM), a key enzyme in the biosynthesis of mycobacterial cell walls, is a potential target for the treatment of tuberculosis. In this work, we investigate binding models of a non‐substrate‐like inhibitor, MS‐208, with M. tuberculosis UGM. Initial saturation transfer difference (STD) NMR experiments indicated a lack of direct competition between MS‐208 and the enzyme substrate, and subsequent kinetic assays showed mixed inhibition. We thus hypothesized that MS‐208 binds at an allosteric binding site (A‐site) instead of the enzyme active site (S‐site). A candidate A‐site was identified in a subsequent computational study, and the overall hypothesis was supported by ensuing mutagenesis studies of the A‐site. Further molecular dynamics studies led us to propose that MS‐208 inhibition occurs by preventing complete closure of an active site mobile loop that is necessary for productive substrate binding. The results suggest the presence of an A‐site with potential druggability, opening up new opportunities for the development of novel drug candidates against tuberculosis.