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Vol. 63, Issue 5, 993-1001, May 2003
Cancer Center and the Department of Molecular Pharmacology and
Experimental Therapeutics, Mayo Clinic Scottsdale, Scottsdale, Arizona
(M.Z., M.D., D.I.P., X.-Q.D., E.M.H., L.J.M.); and Department of
Chemistry and Center for Structural Biology, Vanderbilt University,
Nashville, Tennessee (Z.L., T.P.L.)
The amino-terminal domain of class B G protein-coupled receptors is
critically important for natural peptide agonist binding and action.
The precise role it plays and the molecular basis of the interaction
between ligand and this domain are not well understood. In the current
work, we have developed a new probe for affinity labeling the secretin
receptor through a photolabile benzoyl-phenylalanine residue in
position 13. This represented a high affinity ligand
(Ki = 56 ± 8 nM) that was a
potent full agonist to stimulate cellular cAMP (EC50 = 236 ± 22 pM). It covalently labeled the secretin receptor
saturably in a single site. This was localized to the amino-terminal
domain near the first transmembrane segment using a series of chemical
and enzymatic digestions. Edman degradation sequencing of radiolabeled
cyanogen bromide and skatole digestion products that were attached to
glass beads and further cleaved with endoproteinase Asp-N demonstrated
that the labeled residue represented Val103. This is in
contrast with previous photoaffinity labeling through positions 6, 18, 22, and 26 of secretin that all labeled the distal end of the amino
terminus of this receptor. Together, these five pairs of
residue-residue approximations provide important constraints to better
understand the molecular conformation of the agonist-bound receptor.
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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]
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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]
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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]
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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]
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V. Pham, J. D. Wade, B. W. Purdue, and P. M. Sexton Spatial Proximity between a Photolabile Residue in Position 19 of Salmon Calcitonin and the Amino Terminus of the Human Calcitonin Receptor J. Biol. Chem., February 20, 2004; 279(8): 6720 - 6729. [Abstract] [Full Text] [PDF]
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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]
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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]
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