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

Author(s)

Chung, Injae ; Wright, John J. ; Bridges, Hannah R. ; Ivanov, Bozhidar S. ; Biner, Olivier ; Pereira, Caroline S. ; Arantes, Guilherme M. ; Hirst, Judy

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 13, n. 1, p. 13-pg., 2022-05-19.

Abstract

Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q(10)) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q(10) reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q(10). Using cryo-EM, we reveal a Q(10) 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 Q(10) 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. Using cryo-EM, Chung et al. investigate conformational states of mammalian respiratory complex I to reveal an ubiquinone-10 molecule occupying the full length of the Q-binding channel. Molecular dynamics simulations suggest how the charge states of key residues influence the substrate binding pose. (AU)

• FAPESP's process: 19/21856-7 - Computational molecular bioenergetics
• Grantee: Guilherme Menegon Arantes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/14542-3 - Molecular mechanisms of respiratory complex I
• Grantee: Caroline Simões Pereira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral