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J. Biol. Chem., Vol. 281, Issue 30, 21558-21565, July 28, 2006

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A Missense Mutation in the Seven-transmembrane Domain of the Human Ca²⁺ Receptor Converts a Negative Allosteric Modulator into a Positive Allosteric Modulator^*

Jianxin Hu¹, Jiankang Jiang, Stefano Costanzi^¶, Craig Thomas, Wu Yang^||, Jean H. M. Feyen^||, Kenneth A. Jacobson, and Allen M. Spiegel

From the Molecular Pathophysiology Section, NIDCD, National Institutes of Health, Bethesda, Maryland 20892, the Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Computational Chemistry Core Laboratory, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and the ^||Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543

G protein-coupled receptors (GPCRs) are the most common targets of drug action. Allosteric modulators bind to the seven-transmembrane domain of family 3 GPCRs and offer enhanced selectivity over orthosteric ligands that bind to the large extracellular N terminus. We characterize a novel negative allosteric modulator of the human Ca²⁺ receptor, Compound 1, that retains activity against the E837A mutant that lacks a response to previously described positive and negative modulators. A related compound, JKJ05, acts as a negative allosteric modulator on the wild type receptor but as a positive modulator on the E837A mutant receptor. This positive modulation critically depends on the primary amine in JKJ05, which appears to interact with acidic residue Glu⁷⁶⁷ in our model of the seven-transmembrane domain of the receptor. Our results suggest the need for identification of possible genetic variation in the allosteric site of therapeutically targeted GPCRs.

Received for publication, April 17, 2006 , and in revised form, May 19, 2006.

^* This research was supported by the Intramural Research Program of the NIDCD and NIDDK, National Institutes of Health. 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 methods and supplemental references.

¹ To whom correspondence should be addressed: National Institutes of Health, Bldg. 10, Rm. 8C-101, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-9212; Fax: 301-402-0374; E-mail: jianxinh{at}intra.niddk.nih.gov.

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