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J. Biol. Chem., Vol. 283, Issue 27, 19132-19139, July 4, 2008

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Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor to PGC-1^*

Yong Li¹, Amanda Kovach, Kelly Suino-Powell, Dariusz Martynowski, and H. Eric Xu²

From the Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503 and the Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

The functional interaction between the peroxisome proliferator-activated receptor (PPAR) and its coactivator PGC-1 is crucial for the normal physiology of PPAR and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR ligand-binding domain bound to rosiglitazone and to a large PGC-1 fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1 and the PPAR coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1 is capable of binding to PPAR. Our studies reveal that the strong interaction of PGC-1 and PPAR is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1 indicate that the first PGC-1 motif is necessary and sufficient for PGC-1 to coactivate PPAR in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR and PGC-1 in glucose homeostasis and adipocyte differentiation.

Received for publication, March 13, 2008 , and in revised form, May 8, 2008.

The atomic coordinates and structure factors (code 3CS8) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK071662 and DK066202 (to H. E. X.) and HL089301 (to H. E. X. and Y. L.). This work was also supported by a grant from the Jay and Betty Van Andel Foundation (to H. E. X.), a grant from the Competitive Medical Research Fund of The University of Pittsburgh Medical Center Health System (to Y. L.), and an award from the American Heart Association (to Y. L.). Use of the Advanced Photon Source was supported by the Office of Science of the United States Department of Energy. 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.

¹ To whom correspondence may be addressed: 709 Salk Hall, Pittsburgh, PA 15261. Fax: 412-648-1664; E-mail: yol21{at}pitt.edu.

² To whom correspondence may be addressed: 333 Bostwick Ave., Grand Rapids, MI 49503. Fax: 616-234-5773; E-mail: eric.xu{at}vai.org.

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