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TitleStructural Elucidation of the Mechanism for Inhibitor Resistance in the Na-Translocating NADH-Ubiquinone Oxidoreductase from .
Journal, issue, pagesBiochemistry, Vol. 64, Issue 9, Page 1963-1972, Year 2025
Publish dateMay 6, 2025
AuthorsMoe Ishikawa-Fukuda / Jun-Ichi Kishikawa / Takahiro Masuya / Takeshi Ito / Nicole L Butler / Danielle McFee / Takayuki Kato / Blanca Barquera / Hideto Miyoshi / Masatoshi Murai /
PubMed AbstractNa-translocating NADH-ubiquinone oxidoreductase (Na-NQR) is a unique redox-driven Na-pump. Since this enzyme is exclusively found in prokaryotes, including the human pathogens and , it is a ...Na-translocating NADH-ubiquinone oxidoreductase (Na-NQR) is a unique redox-driven Na-pump. Since this enzyme is exclusively found in prokaryotes, including the human pathogens and , it is a promising target for highly selective antibiotics. Korormicin A, a natural product, and a specific and potent inhibitor of Na-NQR, may become a lead compound for the relevant drug design. We previously showed that the G141A mutation in the NqrB subunit (NqrB-G141A) confers moderate resistance to korormicin A (about 100-fold). However, the efficiency of photoaffinity labeling of the mutant enzyme by a photoreactive korormicin derivative was the same as in the wild-type enzyme. Because of these apparently conflicting results, the molecular mechanism underlying the korormicin A-resistance remains elusive. In the present study, we determined the cryo-EM structure of the NqrB-G141A mutant in the presence of bound korormicin A, and compared it to the corresponding structure from the wild-type enzyme. The toxophoric moiety of korormicin A binds to the mutant enzyme similarly to how it binds to the wild type. However, the added bulk of the alanine-141 excludes the alkyl side chain from the binding cavity, resulting in a decrease in the binding affinity. In fact, isothermal titration calorimetry revealed that the binding affinity of korormicin to the NqrB-G141A mutant is significantly weaker compared to the wild-type. Altogether, we conclude that the inhibitory potency of korormicin A is weaker in the NqrB-G141A mutant due to the decrease in its binding affinity to the altered binding cavity.
External linksBiochemistry / PubMed:40263754 / PubMed Central
MethodsEM (single particle)
Resolution2.68 Å
Structure data

63340

9lrr

EMDB-63340, PDB-9lrr:
Cryo-EM structure of Na+-translocating NADH-ubiquinone oxidoreductase NqrB-G141A mutant from Vibrio cholerae with bound korormicin A
Method: EM (single particle) / Resolution: 2.68 Å

Chemicals

ChemComp-FMN:
FLAVIN MONONUCLEOTIDE

ChemComp-RBF:
RIBOFLAVIN

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-IQT:
Korormicin

ChemComp-CA:
Unknown entry

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

ChemComp-HOH:
WATER

Source
  • vibrio cholerae o395 (bacteria)
KeywordsMEMBRANE PROTEIN / Na+-NQR / Na+ transporter / inhibitor / oxidoreductase / drug resistant

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