Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy

Journal article

Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q₁₀) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q₁₀ reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q₁₀. Using cryo-EM, we reveal a Q₁₀ molecule occupying the full length of the Q-binding site in the 'active' (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q₁₀ binding pose. By comparing ligand-bound and ligand-free forms of the 'deactive' resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.

Authors: Chung, I; Wright, JJ; Bridges, HR; Ivanov, BS; Biner, O

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 2758-2758
• Article number: 2758
• Publication date: 2022-05-19
• DOI: 10.1038/s41467-022-30506-1
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Chemistry; Receptor; Ligand (biochemistry); Stereochemistry; Binding site; Mitochondrion; Biochemistry; Conformational change; Inner mitochondrial membrane; Biophysics; Biology; Oxidative phosphorylation