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J. Biol. Chem., Vol. 282, Issue 40, 29514-29520, October 5, 2007

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Exploring the Ubiquinone Binding Cavity of Respiratory Complex I^*

From the Johann Wolfgang Goethe-Universität, Fachbereich Medizin, Zentrum der Biologischen Chemie, Molekulare Bioenergetik, Centre of Excellence Frankfurt "Macromolecular Complexes", D-60590 Frankfurt am Main, Germany

Proton pumping respiratory complex I is a major player in mitochondrial energy conversion. Yet little is known about the molecular mechanism of this large membrane protein complex. Understanding the details of ubiquinone reduction will be prerequisite for elucidating this mechanism. Based on a recently published partial structure of the bacterial enzyme, we scanned the proposed ubiquinone binding cavity of complex I by site-directed mutagenesis in the strictly aerobic yeast Yarrowia lipolytica. The observed changes in catalytic activity and inhibitor sensitivity followed a consistent pattern and allowed us to define three functionally important regions near the ubiquinone-reducing iron-sulfur cluster N2. We identified a likely entry path for the substrate ubiquinone and defined a region involved in inhibitor binding within the cavity. Finally, we were able to highlight a functionally critical structural motif in the active site that consisted of Tyr-144 in the 49-kDa subunit, surrounded by three conserved hydrophobic residues.

Received for publication, June 1, 2007 , and in revised form, July 16, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft SFB472, Project P2. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Universität Frankfurt, Zentrum der Biologischen Chemie, Molekulare Bioenergetik, Theodor-Stern-Kai 7, Haus 26, D-60590 Frankfurt am Main, Germany. Tel.: 49-69-6301-6926; Fax: 49-69-6301-6970; E-mail: brandt{at}zbc.kgu.de.

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