Conformational coupling of redox-driven Na⁺-translocation in Vibrio cholerae NADH:quinone oxidoreductase

In the respiratory chain, NADH oxidation is coupled to ion translocation across the membrane to build up an electrochemical gradient. In the human pathogen Vibrio cholerae, the sodium-pumping NADH:quinone oxidoreductase (Na⁺-NQR) generates a sodium gradient by a so far unknown mechanism. Here we show that ion pumping in Na⁺-NQR is driven by large conformational changes coupling electron transfer to ion translocation. We have determined a series of cryo-EM and X-ray structures of the Na⁺-NQR that represent snapshots of the catalytic cycle. The six subunits NqrA, B, C, D, E, and F of Na⁺-NQR harbor a unique set of cofactors that shuttle the electrons from NADH twice across the membrane to quinone. The redox state of a unique intramembranous [2Fe-2S] cluster orchestrates the movements of subunit NqrC, which acts as an electron transfer switch. We propose that this switching movement controls the release of Na⁺ from a binding site localized in subunit NqrB.