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J. Biol. Chem., Vol. 281, Issue 48, 36783-36792, December 1, 2006

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Random Mutagenesis of the Complement Factor 5a (C5a) Receptor N Terminus Provides a Structural Constraint for C5a Docking^*

From the Departments of Medicine and Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

The N terminus of G protein-coupled receptors has been implicated in binding to peptide hormones. We have used random saturation mutagenesis to identify essential residues in the N terminus of the human complement factor 5a receptor (C5aR). In a library of N-terminal mutant C5aR molecules screened for activation by C5a, residues 24-30 of the C5aR showed a marked propensity to mutate to cysteine, most likely indicating that sulfhydryl groups at these positions are appropriately situated to form disulfide interactions with the unpaired Cys²⁷ of human C5a. This presumptive spatial constraint allowed the ligand to be computationally docked to the receptor to form a model of the C5a/C5aR interaction. When the N-terminal mutant C5aR library was rescreened with C5a C27R, a ligand incapable of disulfide interactions, no individual position in the N terminus was essential for receptor signaling. However, the region 19-29 was relatively highly conserved in the functional mutants, further demonstrating that this region of the C5aR makes a productive physiologic interaction with the C5a ligand.

Received for publication, August 11, 2006

^* This work was supported by National Institutes of Health Grant R01 GM63720 (to T.J.B.). 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 Recipient of a predoctoral fellowship from the American Heart Association.

² To whom correspondence should be addressed: 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110. Tel.: 314-747-3997; Fax: 314-362-7641; E-mail: baranski{at}wustl.edu.

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