Structure of inhibitor-bound mammalian complex I

DOI: 10.1038/s41467-020-18950-3

Authors: Hannah R. Bridges (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , Justin G. Fedor (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , James N. Blaza (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , Andrea Di Luca (Technische Universität München; Stockholm University) , Alexander Jussupow (Technische Universität München) , Owen D. Jarman (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , John J. Wright (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge; Imperial College London) , Ahmed-Noor A. Agip (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , Ana P. Gamiz-Hernandez (Technische Universität München; Stockholm University) , Maxie M. Roessler (Imperial College London) , Ville R. I. Kaila (Technische Universität München; Stockholm University) , Judy Hirst (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: October 2020
Diamond Proposal Number(s): 16309

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.

Journal Keywords: Bioenergetics; Cryoelectron microscopy; Enzyme mechanisms; Oxidoreductases

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: JC requested microscopes from author.

Added On: 21/10/2020 13:50

Documents:
s41467-020-18950-3.pdf

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)