Now researchers in the Ville Kaila Lab at the Department of Biochemistry and Biophysics (DBB), at Stockholm University together with the Judy Hirst Lab at The Medical Research Council Mitochondrial Biology Unit, at the University of Cambridge, UK, have resolved the first molecular structure of the mammalian mitochondrial complex I from mouse heart with substrate-like inhibitor molecules bound in the active site.

Combining cryo-electron microscopy (cryoEM) experiments with biochemical, spectroscopic, and computational studies, the researchers determined the best resolved structure to date of this mammalian protein with a substrate-mimic in the active site. Their new data shows how the inhibitor blocks the natural substrate binding site at two distinct positions: one located in the hydrophilic electron transfer-module, and the other in the proton-pumping membrane domain. These findings suggest how the substrate molecule could transduce energy by moving along different domains of this large enzyme, and supports mechanistic principles predicted by prior computational work from the Kaila Lab.

The study, published in Nature Communications, elucidates key inhibition and substrate reduction mechanisms that are central for understanding the principles of energy transduction in mammalian complex I. Importantly, this work also brings us closer to understanding how molecular dysfunction leads to the development of human mitochondrial disorders.

This collaborative work was supported by the European Research Council (ERC), the Knut and Alice Wallenberg Foundation (KAW), and the Medical Research Council (MRC).




Structure of inhibitor-bound mammalian complex I

Hannah R. Bridges, Justin G. Fedor, James N. Blaza, Andrea Di Luca, Alexander Jussupow, Owen D. Jarman, John J. Wright, Ahmed-Noor A. Agip, Ana P. Gamiz-Hernandez, Maxie M. Roessler,
Ville R. I. Kaila*, Judy Hirst*. Nature Communications 11, 5261 (2020)

doi: 10.1038/s41467-020-18950-3.