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J. Biol. Chem., Vol. 278, Issue 48, 48300-48312, November 28, 2003

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Spatial Approximation between Two Residues in the Mid-region of Secretin and the Amino Terminus of Its Receptor

INCORPORATION OF SEVEN SETS OF SUCH CONSTRAINTS INTO A THREE-DIMENSIONAL MODEL OF THE AGONIST-BOUND SECRETIN RECEPTOR^*

Maoqing Dong, Zhijun Li¶, Mengwei Zang, Delia I. Pinon, Terry P. Lybrand¶||, and Laurence J. Miller**

From the Cancer Center and the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259 and the ^¶Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232

Photoaffinity labeling of receptors by bound agonists can provide important spatial constraints for molecular modeling of activated receptor complexes. Secretin is a 27-residue peptide hormone with a diffuse pharmacophoric domain that binds to the secretin receptor, a prototypic member of the Class B family of G protein-coupled receptors. In this work, we have developed, characterized, and applied two new photolabile probes for this receptor, with sites for covalent attachment in peptide positions 12 and 14, surrounding the previously most informative site of affinity labeling of this receptor. The [Tyr¹⁰,(BzBz)Lys¹²]rat secretin-27 probe covalently labeled receptor residue Val⁶, whereas the [Tyr¹⁰,(BzBz)Lys¹⁴]rat secretin-27 probe labeled receptor residue Pro³⁸. When combined with previous photoaffinity labeling data, there are now seven independent sets of constraints distributed throughout the peptide and receptor amino-terminal domain that can be used together to generate a new molecular model of the ligand-occupied secretin receptor. The aminoterminal domain of this receptor presented a stable platform for peptide ligand interaction, with the amino terminus of the peptide hormone extended toward the transmembrane helix domain of the receptor. This provides clear insights into the molecular basis of natural ligand binding and supplies testable hypotheses regarding the molecular basis of activation of this receptor.

Received for publication, August 18, 2003 , and in revised form, September 16, 2003.

^* This work was supported by National Institutes of Health Grants DK46577 (to L. J. M.) and NS-33290 (to T. P. L.) and the Fiterman Foundation (to L. J. M.). 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.

Both authors contributed equally to this work.

|| To whom correspondence may be addressed: Dept. of Chemistry and Center for Structural Biology, Vanderbilt University, 5142 Biosciences/MRB III, Nashville, TN 37232. Tel.: 615-343-1247; Fax: 615-936-2211; E-mail: lybrand{at}structbio.vanderbilt.edu. ^** To whom correspondence may be addressed: Cancer Center, Mayo Clinic Scottsdale, 13400 E. Shea Blvd., Scottsdale, AZ 85259. Tel.: 480-301-6650; Fax: 480-301-4596; E-mail: miller{at}mayo.edu.

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