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Crystal structure of the entire respiratory complex I

Nature volume 494, pages 443–448 (2013)Cite this article

Subjects

Abstract

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.

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Figure 1: Structure of the entire complex I from T. thermophilus.
Figure 2: Fold of subunit Nqo8.
Figure 3: E-channel and central hydrophilic axis.
Figure 4: Quinone-reaction chamber.
Figure 5: Proposed coupling mechanism of complex I.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 4HE8 (membrane domain) and 4HEA (entire complex).

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Acknowledgements

This work was funded by the Medical Research Council. We thank the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS) for provision of synchrotron radiation facilities. We are grateful to the staff of beamlines ID29, ID23-2 (ESRF) and X06SA (SLS) for assistance.

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Author notes

  1. John M. Berrisford

    Present address: Present address: European Bioinformatics Institute, Cambridge CB10 1SD, UK.,

Authors and Affiliations

  1. Medical Research Council Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK,

    Rozbeh Baradaran, John M. Berrisford, Gurdeep S. Minhas & Leonid A. Sazanov

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  1. Rozbeh Baradaran
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  3. Gurdeep S. Minhas
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Contributions

R.B. purified and crystallized the intact complex; J.M.B. purified and crystallized the membrane domain; G.S.M. performed co-crystallization and soaks with quinone analogues; all authors collected and analysed X-ray data; L.A.S. designed and supervised the project, analysed data and wrote the manuscript, with contributions from all authors.

Corresponding author

Correspondence to Leonid A. Sazanov.

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The authors declare no competing financial interests.

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Baradaran, R., Berrisford, J., Minhas, G. et al. Crystal structure of the entire respiratory complex I. Nature 494, 443–448 (2013). https://doi.org/10.1038/nature11871

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