Identification of Critical Ligand Binding Determinants in Mycobacterium Tuberculosis Adenosine-5'-phosphosulfate Reductase

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Aug 15

PMID 19678707

Citations 16

Authors

Jiyoung A Hong

Devayani P Bhave

Kate S Carroll

Affiliations

Soon will be listed here.

Abstract

Mycobacterium tuberculosis adenosine-5'-phosphosulfate (APS) reductase is an iron-sulfur protein and a validated target to develop new antitubercular agents, particularly for the treatment of latent infection. To facilitate the development of potent and specific inhibitors of APS reductase, we have probed the molecular determinants that underlie binding and specificity through a series of substrate and product analogues. Our study highlights the importance of specific substitutent groups for substrate binding and provides functional evidence for ligand-specific conformational states. An active site model has been developed for M. tuberculosis APS reductase that is in accord with the results presented here as well as prior structural data reported for Pseudomonas aeruginosa APS reductase and related enzymes. This model illustrates the functional features required for the interaction of APS reductase with a ligand and provides a pharmacological roadmap for the rational design of small molecules as potential inhibitors of APS reductase present in human pathogens, including M. tuberculosis.

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