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J. Biol. Chem., Vol. 281, Issue 6, 3398-3407, February 10, 2006

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Different Residues Mediate Recognition of 1-O-Oleyllysophosphatidic Acid and Rosiglitazone in the Ligand Binding Domain of Peroxisome Proliferator-activated Receptor ^*

Tamotsu Tsukahara, Ryoko Tsukahara, Satoshi Yasuda, Natalia Makarova, William J. Valentine, Patrick Allison^¶, Hongbin Yuan^¶, Daniel L. Baker^||**, Zaiguo Li, Robert Bittman, Abby Parrill^¶, and Gabor Tigyi^**1

From the Departments of Physiology and Pharmaceutical Sciences, University of Tennessee Health Science Center, the Department of Chemistry and ^¶and Computational Research Institute on Materials, University of Memphis, Memphis, Tennessee 38152, the ^||Department of Medicine and the Vascular Biology and Genomics & Bioinformatics Centers of Excellence, ^**University of Tennessee Health Science Center, University of Tennessee Cancer Institute, Memphis, Tennessee 38152, and the Department of Chemistry and Biochemistry, Queens College, City University of New York, New York, New York 11367

Here we showed that a naturally occurring ether analog of lysophosphatidic acid, 1-O-octadecenyl-2-hydroxy-sn-glycero-3-phosphate (AGP), is a high affinity partial agonist of the peroxisome proliferator-activated receptor (PPAR). Binding studies using the PPAR ligand binding domain showed that [³²P]AGP and [³H]rosiglitazone (Rosi) both specifically bind to PPAR and compete with each other. [³²P]AGP bound PPAR with an affinity (K_d(app) 60 nM) similar to that of Rosi. However, AGP displaced 40% of bound [³H]Rosi even when applied at a 2000-fold excess. Activation of PPAR reporter gene expression by AGP and Rosi showed similar potency, yet AGP-mediated activation was 40% that of Rosi. A complex between AGP and PPAR was generated using molecular modeling based on a PPAR crystal structure. AGP-interacting residues were compared with Rosi-interacting residues identified within the Rosi-PPAR co-crystal complex. These comparisons showed that the two ligands occupy partially overlapping positions but make different hydrogen bonding and ion pairing interactions. Site-specific mutants of PPAR were prepared to examine individual ligand binding. H323A and H449A mutants showed reduced binding of Rosi but maintained binding of AGP. In contrast, the R288A showed reduced AGP binding but maintained Rosi binding. Finally, alanine replacement of Tyr-473 abolished binding and activation by Rosi and AGP. These observations indicate that the endogenous lipid mediator AGP is a high affinity ligand of PPAR but that it binds via interactions distinct from those involved in Rosi binding. These distinct interactions are likely responsible for the partial PPAR agonism of AGP.

Received for publication, October 4, 2005 , and in revised form, November 29, 2005.

^* This work was supported by United States Public Health Service Grants CA92160 (to G. T.), HL61469 (to G. T.), HL79004 (to G. T.), HL083187 (to R. B.), and T32 HL007641 (to W. J. V.), the American Heart Association Grants 50006N, 355199B (to A. P.), and 0525489B (to T. T.), and National Science Foundation Grant CHE0353885 (to A. P.). 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 Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-4793; Fax: 901-448-7126; E-mail: gtigyi{at}physio1.utmem.edu.

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