Long-range charge transfer mechanism of the III2IV2 mycobacterial supercomplex

Daniel Riepl, Ana P. Gamiz-Hernandez, Terezia Kovalova, Sylwia M. Król, Sophie L. Mader, Dan Sjöstrand, Martin Högbom, Peter Brzezinski and Ville R. I. Kaila ()
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Daniel Riepl: Stockholm University
Ana P. Gamiz-Hernandez: Stockholm University
Terezia Kovalova: Stockholm University
Sylwia M. Król: Stockholm University
Sophie L. Mader: Stockholm University
Dan Sjöstrand: Stockholm University
Martin Högbom: Stockholm University
Peter Brzezinski: Stockholm University
Ville R. I. Kaila: Stockholm University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest that these energy-transducing enzymes operate as higher-order supercomplexes, but their functional role remains poorly understood and highly debated. Here we resolve the functional dynamics of the 0.7 MDa III2IV2 obligate supercomplex from Mycobacterium smegmatis, a close relative of M. tuberculosis, the causative agent of tuberculosis. By combining computational, biochemical, and high-resolution (2.3 Å) cryo-electron microscopy experiments, we show how the mycobacterial supercomplex catalyses long-range charge transport from its menaquinol oxidation site to the binuclear active site for oxygen reduction. Our data reveal proton and electron pathways responsible for the charge transfer reactions, mechanistic principles of the quinone catalysis, and how unique molecular adaptations, water molecules, and lipid interactions enable the proton-coupled electron transfer (PCET) reactions. Our combined findings provide a mechanistic blueprint of mycobacterial supercomplexes and a basis for developing drugs against pathogenic bacteria.

Date: 2024
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DOI: 10.1038/s41467-024-49628-9

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