Crystal structure of the entire respiratory complex I

• Published in: Nature (London) 2013-02, Vol.494 (7438), p.443-448
• Main Authors: Baradaran, Rozbeh, Berrisford, John M., Minhas, Gurdeep S., Sazanov, Leonid A.
• Format: Article
• Language: English
• Subjects: 631/45/173; 631/45/607; 631/535/1266; 631/57/1464; Benzoquinones - chemistry; Benzoquinones - metabolism; Cell Membrane - metabolism; Crystallography, X-Ray; Crystals; E coli; Electron Transport Complex I - chemistry; Electron Transport Complex I - metabolism; Enzymes; Humanities and Social Sciences; Humans; Hydrophobic and Hydrophilic Interactions; Mitochondrial DNA; Models, Molecular; multidisciplinary; Mutation; NAD - metabolism; Oxidation-Reduction; Protein Folding; Protein Subunits - chemistry; Protein Subunits - metabolism; Proton-Motive Force; Protons; Science; Structure; Structure-activity relationships (Biochemistry); Thermus thermophilus - chemistry; Thermus thermophilus - cytology; Translocation; Ubiquinone - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11871

Complex I is the first and largest enzyme of the respiratory chain and has a central role in cellular energy production through the coupling of NADH:ubiquinone electron transfer to proton translocation. It is also implicated in many common human neurodegenerative diseases. Here, we report the first crystal structure of the entire, intact complex I (from Thermus thermophilus ) at 3.3 Å resolution. The structure of the 536-kDa complex comprises 16 different subunits, with a total of 64 transmembrane helices and 9 iron–sulphur clusters. The core fold of subunit Nqo8 (ND1 in humans) is, unexpectedly, similar to a half-channel of the antiporter-like subunits. Small subunits nearby form a linked second half-channel, which completes the fourth proton-translocation pathway (present in addition to the channels in three antiporter-like subunits). The quinone-binding site is unusually long, narrow and enclosed. The quinone headgroup binds at the deep end of this chamber, near iron–sulphur cluster N2. Notably, the chamber is linked to the fourth channel by a ‘funnel’ of charged residues. The link continues over the entire membrane domain as a flexible central axis of charged and polar residues, and probably has a leading role in the propagation of conformational changes, aided by coupling elements. The structure suggests that a unique, out-of-the-membrane quinone-reaction chamber enables the redox energy to drive concerted long-range conformational changes in the four antiporter-like domains, resulting in translocation of four protons per cycle. The atomic-resolution structure of the entire respiratory complex I is reported, with the resolution high enough to map out the locations and orientations of nearly all amino-acid side chains—some of which link to human neurodegenerative diseases—and reveals which amino-acid interactions take place at the hydrophilic domain–membrane domain interface. Last piece of the respiratory-chain jigsaw Complex I is the first and largest enzyme of the mitochondrial electron transport chain, and until now it was the only component of the respiratory chain without a fully known structure. In this manuscript, the authors present the atomic structure of the entire complex I. The enzyme facilitates the transfer of two electrons from NADH to ubiquinone, coupled to the translocation of four protons across the bacterial or inner-mitochondrial membrane. The structure reveals several unexpected features, including a long reaction chamber that acco