3QDL

Crystal structure of RdxA from Helicobacter pyroli

3QDL の概要

• エントリーDOI: 10.2210/pdb3qdl/pdb
• 分子名称: Oxygen-insensitive NADPH nitroreductase, FLAVIN MONONUCLEOTIDE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: oxygen-insensitive nad(p)h nitroreductase, oxidoreductase
• 由来する生物種: Helicobacter pylori (Campylobacter pylori)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 98413.72

構造登録者

Rojas, A.L.,Martinez-Julvez, M.,Olekhnovich, I.N.,Hoffman, P.S.,Sancho, J. (登録日: 2011-01-18, 公開日: 2012-01-18, 最終更新日: 2023-09-13)

主引用文献

Martinez-Julvez, M.,Rojas, A.L.,Olekhnovich, I.,Espinosa Angarica, V.,Hoffman, P.S.,Sancho, J.
Structure of RdxA--an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori.
Febs J., 279:4306-4317, 2012

PubMed Abstract: The RdxA oxygen-insensitive nitroreductase of the human gastric pathogen Helicobacter pylori is responsible for the susceptibility of this organism to the redox active prodrug metronidazole [2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol]. Loss-of-function mutations in rdxA are primarily responsible for resistance to this therapeutic. RdxA exhibits potent NADPH oxidase activity under aerobic conditions and metronidazole reductase activity under strictly anaerobic conditions. In the present study, we report the crystal structure of RdxA, which is a homodimer exhibiting domain swapping and containing two molecules of FMN bound at the dimer interface. We have found a gap between the side chain of Tyr47 and the isoalloxazine ring of FMN that appears to be appropriate for substrate binding. The structure does not include residues 97-128, which correspond to a locally unstable part of the NTR from Escherichia coli, and might be involved in cofactor binding. Comparison of H. pylori RdxA with other oxidoreductases of known structure suggests that RdxA may belong to a new subgroup of oxidoreductases in which a cysteine side chain close to the FMN cofactor could be involved in the reductive activity. In this respect, the mutation of C159 to A or S (C159A/S) has resulted in a loss of metronidazole reductase activity but not NADPH oxidase activity. The RdxA structure enables the interpretation of the many loss-of-function mutations described previously, including those affecting C159, a residue whose interaction with FMN is required for the nitroreduction of metronidazole. The present studies provide unique insights into the redox behaviour of the flavin in this key enzyme for metronidazole activation, including a potential use in gene therapy.

PubMed: 23039228
DOI: 10.1111/febs.12020

実験手法

X-RAY DIFFRACTION (2 Å)