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J. Biol. Chem., Vol. 282, Issue 5, 3146-3156, February 2, 2007

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Differential Helical Orientations among Related G Protein-coupled Receptors Provide a Novel Mechanism for Selectivity

STUDIES WITH SALVINORIN A AND THE -OPIOID RECEPTOR^*

Timothy A. Vortherms, Philip D. Mosier^¶, Richard B. Westkaemper^¶, and Bryan L. Roth^||**1

From the Departments of Biochemistry, ^||Psychiatry, and ^**Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, the Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, and the ^¶Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298

Salvinorin A, the active component of the hallucinogenic sage Salvia divinorum, is an apparently selective and highly potent -opioid receptor (KOR) agonist. Salvinorin A is unique among ligands for peptidergic G protein-coupled receptors in being nonnitrogenous and lipid-like in character. To examine the molecular basis for the subtype-selective binding of salvinorin A, we utilized an integrated approach using chimeric opioid receptors, site-directed mutagenesis, the substituted cysteine accessibility method, and molecular modeling and dynamics studies. We discovered that helix 2 is required for salvinorin A binding to KOR and that two residues (Val-108(2.53) and Val-118(2.63)) confer subtype selectivity. Intriguingly, molecular modeling studies predicted that these loci exhibit an indirect effect on salvinorin A binding, presumably through rotation of helix 2. Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the -opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility. These findings imply that differences in the helical orientation of helix 2 are critical for the selectivity of salvinorin A binding to KOR and provide a structurally novel basis for ligand selectivity.

Received for publication, September 29, 2006 , and in revised form, November 15, 2006.

^* This work was supported by National Institutes of Health Grants RO1DA017204 (to B. L. R.), 5T32HL007653-17 (to T. A. V.), and 1F32DA022188-01 (to T. A. V.). 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 should be addressed: Dept. of Pharmacology, University of North Carolina, CB# 7365, 8032 Burnett-Womack Bldg., Chapel Hill, NC 27599. Tel.: 919-966-7535; Fax: 919-843-5788; E-mail: bryan_roth{at}med.unc.edu.

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