Cryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae

Jun-ichi Kishikawa, Moe Ishikawa, Takahiro Masuya, Masatoshi Murai, Yuki Kitazumi, Nicole L. Butler, Takayuki Kato, Blanca Barquera and Hideto Miyoshi ()
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Jun-ichi Kishikawa: Osaka University
Moe Ishikawa: Kyoto University
Takahiro Masuya: Kyoto University
Masatoshi Murai: Kyoto University
Yuki Kitazumi: Kyoto University
Nicole L. Butler: Rensselaer Polytechnic Institute
Takayuki Kato: Osaka University
Blanca Barquera: Rensselaer Polytechnic Institute
Hideto Miyoshi: Kyoto University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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 be responsible to reducing the long distance between the 2Fe-2S centers in NqrF and NqrD/E. Two different types of specific inhibitors bind to the N-terminal region of NqrB, which is disordered in the absence of inhibitors. The present study provides a foundation for understanding the function of Na+-NQR and the binding manner of specific inhibitors.

Date: 2022
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DOI: 10.1038/s41467-022-31718-1

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