HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 278/48/48300    most recent M309166200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dong, M. Articles by Miller, L. J. Search for Related Content PubMed PubMed Citation Articles by Dong, M. Articles by Miller, L. J. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Dong, P. C.-H. Lam, D. I. Pinon, P. M. Sexton, R. Abagyan, and L. J. Miller Spatial Approximation between Secretin Residue Five and the Third Extracellular Loop of Its Receptor Provides New Insight into the Molecular Basis of Natural Agonist Binding Mol. Pharmacol., August 1, 2008; 74(2): 413 - 422. [Abstract] [Full Text] [PDF]

				S. Runge, H. Thogersen, K. Madsen, J. Lau, and R. Rudolph Crystal Structure of the Ligand-bound Glucagon-like Peptide-1 Receptor Extracellular Domain J. Biol. Chem., April 25, 2008; 283(17): 11340 - 11347. [Abstract] [Full Text] [PDF]

				K. G. Harikumar, P. C.-H. Lam, M. Dong, P. M. Sexton, R. Abagyan, and L. J. Miller Fluorescence Resonance Energy Transfer Analysis of Secretin Docking to Its Receptor: MAPPING DISTANCES BETWEEN RESIDUES DISTRIBUTED THROUGHOUT THE LIGAND PHARMACOPHORE AND DISTINCT RECEPTOR RESIDUES J. Biol. Chem., November 9, 2007; 282(45): 32834 - 32843. [Abstract] [Full Text] [PDF]

				K. G. Harikumar, D. I. Pinon, and L. J. Miller Transmembrane Segment IV Contributes a Functionally Important Interface for Oligomerization of the Class II G Protein-coupled Secretin Receptor J. Biol. Chem., October 19, 2007; 282(42): 30363 - 30372. [Abstract] [Full Text] [PDF]

				C. S. Lisenbee, K. G. Harikumar, and L. J. Miller Mapping the Architecture of Secretin Receptors with Intramolecular Fluorescence Resonance Energy Transfer Using Acousto-Optic Tunable Filter-Based Spectral Imaging Mol. Endocrinol., August 1, 2007; 21(8): 1997 - 2008. [Abstract] [Full Text] [PDF]

				M. Dong, P. C.-H. Lam, F. Gao, K. Hosohata, D. I. Pinon, P. M. Sexton, R. Abagyan, and L. J. Miller Molecular Approximations between Residues 21 and 23 of Secretin and Its Receptor: Development of a Model for Peptide Docking with the Amino Terminus of the Secretin Receptor Mol. Pharmacol., August 1, 2007; 72(2): 280 - 290. [Abstract] [Full Text] [PDF]

				M. Dong, K. Hosohata, D. I. Pinon, N. Muthukumaraswamy, and L. J. Miller Differential Spatial Approximation between Secretin and Its Receptor Residues in Active and Inactive Conformations Demonstrated by Photoaffinity Labeling Mol. Endocrinol., July 1, 2006; 20(7): 1688 - 1698. [Abstract] [Full Text] [PDF]

				M. Dong, D. I. Pinon, Y. W. Asmann, and L. J. Miller Possible Endogenous Agonist Mechanism for the Activation of Secretin Family G Protein-Coupled Receptors Mol. Pharmacol., July 1, 2006; 70(1): 206 - 213. [Abstract] [Full Text] [PDF]

				K. G. Harikumar, K. Hosohata, D. I. Pinon, and L. J. Miller Use of Probes with Fluorescence Indicator Distributed throughout the Pharmacophore to Examine the Peptide Agonist-binding Environment of the Family B G Protein-coupled Secretin Receptor J. Biol. Chem., February 3, 2006; 281(5): 2543 - 2550. [Abstract] [Full Text] [PDF]

				M. Dong, D. I. Pinon, and L. J. Miller Insights into the Structure and Molecular Basis of Ligand Docking to the G Protein-Coupled Secretin Receptor Using Charge-Modified Amino-Terminal Agonist Probes Mol. Endocrinol., July 1, 2005; 19(7): 1821 - 1836. [Abstract] [Full Text] [PDF]

				C. S. Lisenbee, M. Dong, and L. J. Miller Paired Cysteine Mutagenesis to Establish the Pattern of Disulfide Bonds in the Functional Intact Secretin Receptor J. Biol. Chem., April 1, 2005; 280(13): 12330 - 12338. [Abstract] [Full Text] [PDF]

				M. Dong, D. I. Pinon, R. F. Cox, and L. J. Miller Molecular Approximation between a Residue in the Amino-terminal Region of Calcitonin and the Third Extracellular Loop of the Class B G Protein-coupled Calcitonin Receptor J. Biol. Chem., July 23, 2004; 279(30): 31177 - 31182. [Abstract] [Full Text] [PDF]

				M. Dong, Z. Li, D. I. Pinon, T. P. Lybrand, and L. J. Miller Spatial Approximation between the Amino Terminus of a Peptide Agonist and the Top of the Sixth Transmembrane Segment of the Secretin Receptor J. Biol. Chem., January 23, 2004; 279(4): 2894 - 2903. [Abstract] [Full Text] [PDF]

				M. Dong, D. I. Pinon, R. F. Cox, and L. J. Miller Importance of the Amino Terminus in Secretin Family G Protein-coupled Receptors: INTRINSIC PHOTOAFFINITY LABELING ESTABLISHES INITIAL DOCKING CONSTRAINTS FOR THE CALCITONIN RECEPTOR J. Biol. Chem., January 9, 2004; 279(2): 1167 - 1175. [Abstract] [Full Text] [PDF]