7B93

Cryo-EM structure of mitochondrial complex I from Mus musculus inhibited by IACS-2858 at 3.0 A

Summary for 7B93

• Entry DOI: 10.2210/pdb7b93/pdb
• EMDB information: 12095
• Descriptor: NADH-ubiquinone oxidoreductase chain 3, NADH-ubiquinone oxidoreductase chain 6, NADH-ubiquinone oxidoreductase chain 4L, ... (55 entities in total)
• Functional Keywords: inhibitor, ubiquinone, complex i, oxidoreductase
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 45
• Total formula weight: 1072857.40

Authors

Chung, I.,Hirst, J. (deposition date: 2020-12-14, release date: 2021-05-26, Last modification date: 2025-04-09)

Primary citation

Chung, I.,Serreli, R.,Cross, J.B.,Di Francesco, M.E.,Marszalek, J.R.,Hirst, J.
Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.
Sci Adv, 7:-, 2021

PubMed Abstract: Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.

PubMed: 33990335
DOI: 10.1126/sciadv.abg4000

Experimental method

ELECTRON MICROSCOPY (3.04 Å)