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.
Highlights
Mitochondrial complex I {NADH [reduced form of nicotinamide adenine dinucleotide (NAD+)]:ubiquinone oxidoreductase} (1, 2) is an essential enzyme for mitochondrial energy metabolism that couples oxidative phosphorylation for adenosine 5′-triphosphate (ATP) synthesis to regeneration of NAD+ for the tricarboxylic acid cycle and fatty acid oxidation
While specific mutations in complex I genes cause a host of primary mitochondrial disorders, complex I is further implicated in common pathologies such as ischemia- reperfusion (IR) injury [initiated by a burst of reactive oxygen species (ROS) generated at complex I via reverse electron transport (RET)], metabolic disorders including insulin resistance (3), and subsets of cancers reliant on oxidative phosphorylation (4)
The extent of inhibition of the isolated IACS-2858–bound enzyme was 81 ± 5% for the sample used for cryo–electron microscopy (cryo-EM) analyses, by comparing its initial turnover rate with that of a matching control sample prepared without inhibitor
Summary
Mitochondrial complex I {NADH [reduced form of nicotinamide adenine dinucleotide (NAD+)]:ubiquinone oxidoreductase} (1, 2) is an essential enzyme for mitochondrial energy metabolism that couples oxidative phosphorylation for adenosine 5′-triphosphate (ATP) synthesis to regeneration of NAD+ for the tricarboxylic acid cycle and fatty acid oxidation. While specific mutations in complex I genes cause a host of primary mitochondrial disorders, complex I is further implicated in common pathologies such as ischemia- reperfusion (IR) injury [initiated by a burst of reactive oxygen species (ROS) generated at complex I via reverse electron transport (RET)], metabolic disorders including insulin resistance (3), and subsets of cancers reliant on oxidative phosphorylation (4). Complex I is increasingly recognized as a promising target for therapeutic intervention through the development of pharmaco logically relevant inhibitors of the enzyme. The S1QEL (suppressors of site IQ electron leak) inhibitors (5) are reported to block ROS production at complex I during RET, and mitochondria-targeted thiol species that react with the deactive state of complex I formed during ischemia have been shown to be protective against IR injury (6). Complex I is a major contributor to drug-induced mitochondrial dysfunction, for example, by antipsychotics (15), through increased oxidative
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call