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J. Biol. Chem., Vol. 278, Issue 47, 47136-47144, November 21, 2003

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Lipid Bilayer Simulations of CXCR4 with Inverse Agonists and Weak Partial Agonists^*

John O. Trent¶||, Zi-xuan Wang**, James L. Murray**, Wenhai Shao, Hirokazu Tamamura, Nobutaka Fujii, and Stephen C. Peiper**

From the J. G. Brown Modeling Facility, Brown Cancer Center, ^¶Department of Medicine, University of Louisville, Louisville, Kentucky 40202, the ^**Department of Pathology and Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, and the Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

CXCR4 is a G protein-coupled receptor (GPCR) that has multiple critical functions in normal and pathologic physiology that include regulation of the metastatic behavior of mammary carcinoma, and utilization as a coreceptor for infection by T-tropic strains of human immunodeficiency virus-1. Molecular dynamic simulations of the rhodopsin-based homology model of CXCR4 were performed in a solvated lipid bilayer to reproduce the microenvironment of this integral membrane protein. The amino acids in CXCR4 necessary for interaction with an inverse agonist, T140, and a weak partial agonist, AMD3100, identified by alanine scanning mutants, were spatially consistent when computationally docked. Whereas T140 binds residues in extracellular domains and regions of the hydrophobic core proximal to the cell surface, amino acids in the central hydrophobic core are critical to binding of AMD3100. The physical localization of T140 binding to CXCR4 by biochemical analyses corroborated the molecular and computational approaches. The structural basis for the interaction of T140 and AMD3100 with CXCR4 confirms that the mechanisms used by these agents are different. This complementary utilization of molecular, physical, and computation analysis provides a powerful approach to elucidate GPCR conformation.

Received for publication, July 21, 2003 , and in revised form, September 3, 2003.

^* This work was supported by National Institutes of Health Grant R01 AI41346 (to S. C. P.), the Georgia Cancer Coalition (to S. C. P.), United States Department of Defense Grant DAMD17-02-1-0446 (to J. O. T.), and the Philip Morris External Research Program. 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.

|| To whom correspondence may be addressed: 323 Brown Cancer Center, University of Louisville, 529 S. Jackson St., Louisville, KY 40202. Tel.: 502-852-2194; Fax: 502-852-2195; E-mail: john.trent{at}louisville.edu. To whom correspondence may be addressed. E-mail: speiper{at}mail.mcg.edu.

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