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J. Biol. Chem., Vol. 279, Issue 41, 42383-42392, October 8, 2004

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Identification of CC Chemokine Receptor 7 Residues Important for Receptor Activation^*

Thomas R. Ott, Anil Pahuja, Sarah A. Nickolls¶, David G. Alleva, and R. Scott Struthers||

From the Departments of Exploratory Discovery, Molecular Medicine, and ^¶Molecular Biology, Neurocrine Biosciences, San Diego, California 92130

The binding pocket of family A GPCRs that bind small biogenic amines is well characterized. In this study we identify residues on CC chemokine receptor 7 (CCR-7) that are involved in agonist-mediated receptor activation but not in high affinity ligand binding. The mutations also affect the ability of the ligands to induce chemotaxis. Two of the residues, Lys^{3.33 (137)} and Gln^{5.42 (227)}, are consistent with the binding pocket described for biogenic amines, while Lys^{3.26 (130)} and Asn^{7.32 (305)}, are found at, or close to, the cell surface. Our observations are in agreement with findings from other peptide and chemokine receptors, which indicate that receptors that bind larger ligands contain contact sites closer to the cell surface in addition to the conventional transmembrane binding pocket. These findings also support the theory that chemokine receptors require different sets of interactions for high affinity ligand binding and receptor activation.

Received for publication, January 31, 2004 , and in revised form, July 15, 2004.

^* 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 should be addressed. Tel.: 858-617-7600; Fax: 858-617-7602; E-mail: sstruthers{at}neurocrine.com.

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