High-resolution structure of the antibiotic resistance protein NimA from Deinococcus radiodurans.
Many anaerobic human pathogenic bacteria are treated using 5-nitroimidazole-based (5-Ni) antibiotics, a class of inactive prodrugs that contain a nitro group. The nitro group must be activated in an anaerobic one-electron reduction and is therefore dependent on the redox system in the target cells. Antibiotic resistance towards 5-Ni drugs is found to be related to the nim genes (nimA, nimB, nimC, nimD, nimE and nimF), which are proposed to encode a reductase that is responsible for converting the nitro group of the antibiotic into a nonbactericidal amine. A mechanism for the Nim enzyme has been proposed in which two-electron reduction of the nitro group leads to the generation of nontoxic derivatives and confers resistance against these antibiotics. The cofactor was found to be important in the mechanism and was found to be covalently linked to the reactive His71. In this paper, the 1.2 A atomic resolution crystal structure of the 5-nitroimidazole antibiotic resistance protein NimA from Deinococcus radiodurans (DrNimA) is presented. A planar cofactor is clearly visible and well defined in the electron-density map adjacent to His71, the identification of the cofactor and its properties are discussed.
Leiros
Hanna Kirsti S
HK
The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway. hanna-kirsti.leiros@chem.uit.no
Tedesco
Consiglia
C
McSweeney
Seán M
SM
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D018360:Crystallography, X-Ray; D034301:Deinococcus / Q000737:chemistry*; D019281:Dimerization; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005798:Genes, Bacterial; D006639:Histidine / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009593:Nitroimidazoles / Q000737:chemistry*; D011355:Prodrugs / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D019289:Pyruvic Acid / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014867:Water / Q000737:chemistry
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009593:Nitroimidazoles; D011355:Prodrugs; D014867:Water; D006639:Histidine; D019289:Pyruvic Acid