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The Na⁺-pumping NADH-ubiquinone oxidoreductase (Na⁺-NQR) couples electron transfer from NADH to ubiquinone with Na⁺-pumping, generating an electrochemical Na⁺ gradient that is essential for energy-consuming reactions in bacteria. Since Na⁺-NQR is exclusively found in prokaryotes, it is a promising target for highly selective antibiotics. However, the molecular mechanism of inhibition is not well-understood for lack of the atomic structural information about an inhibitor-bound state. Here we present cryo-electron microscopy structures of Na⁺-NQR from Vibrio cholerae with or without a bound inhibitor at 2.5- to 3.1-Å resolution. The structures reveal the arrangement of all six redox cofactors including a herein identified 2Fe-2S cluster located between the NqrD and NqrE subunits. A large part of the hydrophilic NqrF is barely visible in the density map, suggesting a high degree of flexibility. This flexibility may …