Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824 |
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Authors: | Cellitti Susan E Shaffer Jennifer Jones David H Mukherjee Tathagata Gurumurthy Meera Bursulaya Badry Boshoff Helena I Choi Inhee Nayyar Amit Lee Yong Sok Cherian Joseph Niyomrattanakit Pornwaratt Dick Thomas Manjunatha Ujjini H Barry Clifton E Spraggon Glen Geierstanger Bernhard H |
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Institution: | Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121-1125, USA. |
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Abstract: | Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F(420) deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F(420) and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data. |
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