1W3P

NimA from D. radiodurans with a His71-Pyruvate residue

Summary for 1W3P

• Entry DOI: 10.2210/pdb1w3p/pdb
• Related: 1W3O 1W3Q 1W3R
• Descriptor: NIMA-RELATED PROTEIN, PYRUVIC ACID, ACETATE ION, ... (4 entities in total)
• Functional Keywords: antibiotic resistance, deinococcus radiodurans, 5-nitroimidazole resistance, nim gene, catalytic mechanism
• Biological source: DEINOCOCCUS RADIODURANS
• Total number of polymer chains: 1
• Total formula weight: 24614.34

Authors

Leiros, H.-K.S.,Kozielski-Stuhrmann, S.,Kapp, U.,Terradot, L.,Leonard, G.A.,McSweeney, S.M. (deposition date: 2004-07-17, release date: 2004-10-18, Last modification date: 2023-12-13)

Primary citation

Leiros, H.-K.S.,Kozielski-Stuhrmann, S.,Kapp, U.,Terradot, L.,Leonard, G.A.,Mcsweeney, S.M.
Structural Basis of 5-Nitroimidazole Antibiotic Resistance: The Crystal Structure of Nima from Deinococcus Radiodurans
J.Biol.Chem., 279:55840-, 2004

PubMed Abstract: 5-Nitroimidazole-based antibiotics are compounds extensively used for treating infections in humans and animals caused by several important pathogens. They are administered as prodrugs, and their activation depends upon an anaerobic 1-electron reduction of the nitro group by a reduction pathway in the cells. Bacterial resistance toward these drugs is thought to be caused by decreased drug uptake and/or an altered reduction efficiency. One class of resistant strains, identified in Bacteroides, has been shown to carry Nim genes (NimA, -B, -C, -D, and -E), which encode for reductases that convert the nitro group on the antibiotic into a non-bactericidal amine. In this paper, we have described the crystal structure of NimA from Deinococcus radiodurans (drNimA) at 1.6 A resolution. We have shown that drNimA is a homodimer in which each monomer adopts a beta-barrel fold. We have identified the catalytically important His-71 along with the cofactor pyruvate and antibiotic binding sites, all of which are found at the monomer-monomer interface. We have reported three additional crystal structures of drNimA, one in which the antibiotic metronidazole is bound to the protein, one with pyruvate covalently bound to His-71, and one with lactate covalently bound to His-71. Based on these structures, a reaction mechanism has been proposed in which the 2-electron reduction of the antibiotic prevents accumulation of the toxic nitro radical. This mechanism suggests that Nim proteins form a new class of reductases, conferring resistance against 5-nitroimidazole-based antibiotics.

PubMed: 15492014
DOI: 10.1074/JBC.M408044200

Experimental method

X-RAY DIFFRACTION (1.8 Å)