(−)-Bactobolin A and selected related natural products.
(A) Overall structure of ovine complex I. Core subunits necessary for the reaction of complex I are labeled with corresponding colors, and mammalian supernumerary subunits are shown in gray. NADH and quinone binding sites are indicated. The membrane arm contains four separate proton-pumping channels: three in the antiporter-like subunits ND2, ND4, and ND5 and one in the E-channel, composed of subunits ND1, ND6, and ND4L. Q, quinone.
Leonid A. Sazanov Research Group
Complex I is the first and, with 45 subunits and a total mass of ~1 MDa, the most elaborate of the mitochondrial electron transfer chain enzymes. Complex I converts energy stored in chemical bonds into a proton gradient across the membrane that drives the synthesis of adenosine triphosphate (ATP), the universal energy currency of the cell. In each catalytic cycle, the transfer of two electrons from nicotinamide adenine dinucleotide (NADH) to a hydrophobic electron carrier quinone, which happens in the peripheral arm of the enzyme, is coupled to the translocation of four protons across the inner mitochondrial membrane in the membrane arm. The exact mechanism of this energy conversion currently presents an enigma because of complex I’s size and the spatial separation between the two reactions.
To understand the coupling mechanism of complex I, we solved its cryo–electron microscopy (cryo-EM) structures in five different conditions, including the substrate- and inhibitor-bound states and during active turnover, unlocking the various conformations that the enzyme goes through during the catalytic cycle. We also improved the resolution to up to 2.3 to 2.5 Å, allowing us to directly observe water molecules critical for proton pumping.
Kampjut, D. & Sazanov, L. A. The coupling mechanism of mammalian respiratory complex I, Science, 2020, 370, eabc4209, https://doi.org/10.1126/science.abc4209