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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824
Structure, Volume 20, No. 1, Year 2012
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Description
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. © 2012 Elsevier Ltd.
Authors & Co-Authors
Gurumurthy, Meera
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Boshoff, Helena Ingrid M.
United States, Bethesda
National Institutes of Health Nih
Nayyar, Amit
United States, Bethesda
National Institutes of Health Nih
Cherian, Joseph
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Dick, Thomas
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Manjunatha, Ujjini H.
Singapore, Singapore City
Novartis Institute for Tropical Diseases Pte. Ltd.
Barry, Clifton Earl
United States, Bethesda
National Institutes of Health Nih
Statistics
Citations: 70
Authors: 7
Affiliations: 3
Identifiers
Doi:
10.1016/j.str.2011.11.001
ISSN:
18784186
Research Areas
Health System And Policy