title: Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I.
abstract: Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.
authors.affiliation: Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany. Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl.
authors.forename: Volker
authors.initials: V
authors.lastname: Zickermann
authors.affiliation: Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Christophe
authors.initials: C
authors.lastname: Wirth
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Nasiri
authors.affiliation: Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Siegmund
authors.affiliation: Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
authors.affiliation: Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl.
authors.forename: Carola
authors.initials: C
authors.lastname: Hunte
authors.affiliation: Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D042967:Electron Transport Complex I / Q000737:chemistry* / Q000648:ultrastructure; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000201:enzymology*; D017433:Protein Structure, Secondary; D011522:Protons; D014451:Ubiquinone / Q000737:chemistry; D025062:Yarrowia / Q000201:enzymology
chemical_list: D011522:Protons; D014451:Ubiquinone; D042967:Electron Transport Complex I