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Papers In Press, published online ahead of print May 17, 2005
Molecular & Structural Biology Division, Central Drug Research Institute, Lucknow, U.P. 226001
Corresponding Author: ravi_anitha{at}yahoo.com
DNA ligases utilize either ATP or NAD+ as co-factors to catalyze the formation of phosphodiester bonds in nicked DNA. Those utilizing NAD+ are attractive drug targets because of the unique co-factor requirement for ligase activity. We report here the crystal structure of the adenylation domain of the M.tuberculosis NAD+ -dependent ligase with bound AMP. The adenosine nucleoside moiety of AMP adopts a syn conformation. The structure also captures a new spatial disposition between the two sub-domains of the adenylation domain. Based on the crystal structure and an in-house compound library we have identified a novel class of inhibitors for the enzyme using in-silico docking calculations. The glycosyl ureides based inhibitors are able to distinguish between NAD+ and ATP-dependent ligases as evidenced by in vitro assays against T4 and human DNA ligase I also. Moreover, assays involving an E. coli strain harboring a temperature sensitive ligase mutant and an S. typhimurium ligase deficient strain suggest that the bactericidal activity of the inhibitors is due to inhibition of the essential ligase enzyme. The reported results can be used as the basis for rational design of novel antibacterials.
J. Biol. Chem, 10.1074/jbc.M503780200
Submitted on April 7, 2005
Revised on May 10, 2005
Accepted on May 17, 2005
NAD+ -dependent DNA ligase (Rv3014c)from M.tuberculosis: Crystal structure of the adenylation domain and identification of novel inhibitors
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