Structure of inhibitor-bound mammalian complex I
Jarman, Owen D.
Wright, John J.
Agip, Ahmed-Noor A.
Nature Publishing Group UK
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Bridges, H. R., Fedor, J. G., Blaza, J. N., Di Luca, A., Jussupow, A., Jarman, O. D., Wright, J. J., et al. (2020). Structure of inhibitor-bound mammalian complex I. Nature Communications, 11 (1) https://doi.org/10.1038/s41467-020-18950-3
Funder: The Swedish National Infrastructure for Computing (SNIC, 2019/2-3) UK National Electron Bio-Imaging Centre (eBIC) at the Diamond Light Source, proposal EM16309, funded by the Wellcome Trust, MRC and BBSRC
Abstract: Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I.
Article, /631/45/173, /631/45/607/1168, /631/1647/328/1259, /631/57/1464, /631/535/1258/1259, /119, /101/28, article
RCUK | MRC | Medical Research Foundation (MC_U105663141, MC_UU_00015/2)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (715311)
Royal Society (PGS-R1-191215)
Wellcome Trust (Wellcome) (108466/Z/15/Z)
Partnership for Advanced Computing in Europe AISBL (PRACE) (2018194738)
External DOI: https://doi.org/10.1038/s41467-020-18950-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329545