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Structure of inhibitor-bound mammalian complex I.

<div class='caption-title'>Piericidin bound in the structure of mammalian complex I.</div>
<div class='caption-title'>Cryo-EM densities for the piericidin molecule, and interactions between the protein and the bound piericidin.</div>
<div class='caption-title'>Molecular dynamics simulations of piericidin in complex I.</div>
Bridges HR, Fedor JG, Blaza JN, Di Luca A, Jussupow A, Jarman OD, Wright JJ, Agip AA, Gamiz-Hernandez AP, Roessler MM, Kaila VRI, Hirst J
OpenAccess logo Nat Commun 11 5261 (2020)
Cited: 48 times
EuropePMC logo PMID: 33067417

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.

Reviews - 6ztq mentioned but not cited (2)

  1. Ubiquinone Binding and Reduction by Complex I-Open Questions and Mechanistic Implications. Galemou Yoga E, Schiller J, Zickermann V. Front Chem 9 672851 (2021)
  2. Binding of Natural Inhibitors to Respiratory Complex I. Schiller J, Zickermann V. Pharmaceuticals (Basel) 15 1088 (2022)

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  4. Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I. Grba DN, Blaza JN, Bridges HR, Agip AA, Yin Z, Murai M, Miyoshi H, Hirst J. J Biol Chem 298 101602 (2022)
  5. Quinone Catalysis Modulates Proton Transfer Reactions in the Membrane Domain of Respiratory Complex I. Kim H, Saura P, Pöverlein MC, Gamiz-Hernandez AP, Kaila VRI. J Am Chem Soc 145 17075-17086 (2023)
  6. Functional Water Wires Catalyze Long-Range Proton Pumping in the Mammalian Respiratory Complex I. Röpke M, Saura P, Riepl D, Pöverlein MC, Kaila VRI. J Am Chem Soc 142 21758-21766 (2020)
  7. Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I. Grba DN, Chung I, Bridges HR, Agip AA, Hirst J. Sci Adv 9 eadi1359 (2023)


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  2. Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology. Ježek P, Jabůrek M, Holendová B, Engstová H, Dlasková A. Antioxid Redox Signal 39 635-683 (2023)
  3. Fostering discoveries in the era of exascale computing: How the next generation of supercomputers empowers computational and experimental biophysics alike. Melo MCR, Bernardi RC. Biophys J 122 2833-2840 (2023)
  4. Making the leap from structure to mechanism: are the open states of mammalian complex I identified by cryoEM resting states or catalytic intermediates? Chung I, Grba DN, Wright JJ, Hirst J. Curr Opin Struct Biol 77 102447 (2022)
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  6. Mitochondrial complex I ROS production and redox signaling in hypoxia. Okoye CN, Koren SA, Wojtovich AP. Redox Biol 67 102926 (2023)
  7. The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I. Padavannil A, Ayala-Hernandez MG, Castellanos-Silva EA, Letts JA. Front Mol Biosci 8 798353 (2021)
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