3R5L

Structure of Ddn, the Deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824

Summary for 3R5L

• Entry DOI: 10.2210/pdb3r5l/pdb
• Related: 3R5P 3R5R 3R5W 3R5Y 3R5Z
• Descriptor: Deazaflavin-dependent nitroreductase, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID (3 entities in total)
• Functional Keywords: pa-824, split barrel-like fold, duf385, deazaflavin-dependent nitroreductase, nitroimidazoles, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 14003.58

Authors

Cellitti, S.E.,Shaffer, J.,Jones, D.H.,Mukherjee, T.,Gurumurthy, M.,Bursulaya, B.,Boshoff, H.I.M.,Choi, I.,Nayyar, A.,Lee, Y.S.,Cherian, J.,Niyomrattanakit, P.,Dick, T.,Manjunatha, U.H.,Barry, C.E.,Spraggon, G.,Geierstanger, B.H. (deposition date: 2011-03-18, release date: 2012-01-18, Last modification date: 2024-10-16)

Primary citation

Cellitti, S.E.,Shaffer, J.,Jones, D.H.,Mukherjee, T.,Gurumurthy, M.,Bursulaya, B.,Boshoff, H.I.,Choi, I.,Nayyar, A.,Lee, Y.S.,Cherian, J.,Niyomrattanakit, P.,Dick, T.,Manjunatha, U.H.,Barry, C.E.,Spraggon, G.,Geierstanger, B.H.
Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824.
Structure, 20:101-112, 2012

PubMed 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.

PubMed: 22244759
DOI: 10.1016/j.str.2011.11.001

Experimental method

X-RAY DIFFRACTION (1.55 Å)