|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 275, Issue 1, 9-17, January 7, 2000
From the Division of Bone and Mineral Metabolism, Charles A. Dana
and Thorndike Laboratories, Department of Medicine, Beth Israel
Deaconess Medical Center and Harvard Medical School,
Boston, Massachusetts 02215
Analogs of parathyroid hormone (PTH)-related
protein (PTHrP), singularly substituted with a photoreactive
L-p-benzoylphenylalanine (Bpa) at each of
the first 6 N-terminal positions, were pharmacologically evaluated in
human embryonic kidney cells stably expressing the recombinant human
PTH/PTHrP receptor. Two of these analogs, in which the photoreactive
residue is either in position 1 or 2 (Bpa1- and
Bpa2-PTHrP, respectively) displayed high affinity binding.
Bpa1-PTHrP also displayed high efficacy for the stimulation
of increased cAMP levels. Surprisingly, Bpa2-PTHrP was
found to be a potent antagonist, despite the presence of the principal
activation domain (sequence 1-6). Analysis of the digestion profiles
of the ligand-receptor photoconjugates revealed that both the agonist
and the antagonist cross-link to the S-CH3 group of
Met425 in transmembrane domain 6 of the human PTH/PTHrP
receptor. However, the antagonist Bpa2-PTHrP also
cross-links to a proximal site within the receptor domain
Pro415-Met425. Unlike the antagonist
Bpa2-PTHrP, the potent agonist Bpa2-PTH, also
bearing the Bpa residue in position 2, cross-links only to the
S-CH3 group of Met425 (similar to
Bpa1-PTHrP and Bpa1-PTH). Taken together, these
results suggest that the antagonist Bpa2-PTHrP is able to
distinguish between two distinct conformations of the receptor. The
comparison between PTHrP analogs substituted by Bpa at two consecutive
positions and across PTH and PTHrP reveals insights into the PTH/PTHrP
ligand-receptor bimolecular interaction at the level of a single amino acid.
Photoaffinity Cross-linking Identifies Differences in the
Interactions of an Agonist and an Antagonist with the Parathyroid
Hormone/Parathyroid Hormone-related Protein Receptor*
,
*
This work was supported in part by Grant RO1-DK47940 (to
M. R.) from the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
This work is presented in partial fulfillment of the requirements
of a Ph.D. thesis.
§
To whom correspondence should be addressed: Division of Bone and
Mineral Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave. (HIM 944), Boston, MA 02215. Tel.: 617-667-0901; Fax: 617-667-4432; E-mail: mchorev@warren.med.harvard.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  T. J. Gardella Mimetic Ligands for the PTHR1: Approaches, Developments, and Considerations IBMS BoneKEy, February 1, 2009; 6(2): 71 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Assil-Kishawi, T. A. Samra, D. F. Mierke, and A. B. Abou-Samra Residue 17 of Sauvagine Cross-links to the First Transmembrane Domain of Corticotropin-releasing Factor Receptor 1 (CRFR1) J. Biol. Chem., December 19, 2008; 283(51): 35644 - 35651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. Carter, R.-Q. Liu, W. R. Foster, J. A. Tamasi, A. J. Tebben, M. Favata, A. Staal, M. E. Cvijic, M. H. French, V. Dell, et al. Discovery of a small molecule antagonist of the parathyroid hormone receptor by using an N-terminal parathyroid hormone peptide probe PNAS, April 17, 2007; 104(16): 6846 - 6851. [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]
|
|
|
|
|
|
T. Dean, A. Linglart, M. J. Mahon, M. Bastepe, H. Juppner, J. T. Potts Jr., and T. J. Gardella Mechanisms of Ligand Binding to the Parathyroid Hormone (PTH)/PTH-Related Protein Receptor: Selectivity of a Modified PTH(1-15) Radioligand for G{alpha}S-Coupled Receptor Conformations Mol. Endocrinol., April 1, 2006; 20(4): 931 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Pham, M. Dong, J. D. Wade, L. J. Miller, C. J. Morton, H.-l. Ng, M. W. Parker, and P. M. Sexton Insights into Interactions between the {alpha}-Helical Region of the Salmon Calcitonin Antagonists and the Human Calcitonin Receptor using Photoaffinity Labeling J. Biol. Chem., August 5, 2005; 280(31): 28610 - 28622. [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]
|
|
|
|
|
|
N. Shimizu, T. Dean, J. C. Tsang, A. Khatri, J. T Potts Jr, and T. J. Gardella Novel Parathyroid Hormone (PTH) Antagonists That Bind to the Juxtamembrane Portion of the PTH/PTH-related Protein Receptor J. Biol. Chem., January 21, 2005; 280(3): 1797 - 1807. [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]
|
|
|
|
 |
|
 R. C. Gensure, B. Ponugoti, Y. Gunes, M. R. Papasani, B. Lanske, M. Bastepe, D. A. Rubin, and H. Juppner Identification and Characterization of Two Parathyroid Hormone-Like Molecules in Zebrafish Endocrinology, April 1, 2004; 145(4): 1634 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R. C. Gensure, N. Shimizu, J. Tsang, and T. J. Gardella Identification of a Contact Site for Residue 19 of Parathyroid Hormone (PTH) and PTH-Related Protein Analogs in Transmembrane Domain Two of the Type 1 PTH Receptor Mol. Endocrinol., December 1, 2003; 17(12): 2647 - 2658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dong, Z. Li, M. Zang, D. I. Pinon, T. P. Lybrand, and L. J. Miller 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 J. Biol. Chem., November 28, 2003; 278(48): 48300 - 48312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Sachon, G. Bolbach, G. Chassaing, S. Lavielle, and S. Sagan Cgamma H2 of Met174 Side Chain Is the Site of Covalent Attachment of a Substance P Analog Photoactivable in Position 5 J. Biol. Chem., December 20, 2002; 277(52): 50409 - 50414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bisello, M. Chorev, M. Rosenblatt, L. Monticelli, D. F. Mierke, and S. L. Ferrari Selective Ligand-induced Stabilization of Active and Desensitized Parathyroid Hormone Type 1 Receptor Conformations J. Biol. Chem., October 4, 2002; 277(41): 38524 - 38530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Jahn, K. Eckart, O. Brauns, H. Tezval, and J. Spiess The binding protein of corticotropin-releasing factor: Ligand-binding site and subunit structure PNAS, September 17, 2002; 99(19): 12055 - 12060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Gensure, P. H. Carter, B. D. Petroni, H. Juppner, and T. J. Gardella Identification of Determinants of Inverse Agonism in a Constitutively Active Parathyroid Hormone/Parathyroid Hormone-related Peptide Receptor by Photoaffinity Cross-linking and Mutational Analysis J. Biol. Chem., November 9, 2001; 276(46): 42692 - 42699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, P. H. Carter, A. Khatri, J. T. Potts Jr., and T. J. Gardella Enhanced Activity in Parathyroid Hormone-(1-14) and -(1-11): Novel Peptides for Probing Ligand-Receptor Interactions Endocrinology, July 1, 2001; 142(7): 3068 - 3074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Carter, B. D. Petroni, R. C. Gensure, E. Schipani, J. T. Potts Jr., and T. J. Gardella Selective and Nonselective Inverse Agonists for Constitutively Active Type-1 Parathyroid Hormone Receptors: Evidence for Altered Receptor Conformations Endocrinology, April 1, 2001; 142(4): 1534 - 1545. [Abstract] [Full Text]
|
|
|
|
|
|
K. B. Jonsson, M. R. John, R. C. Gensure, T. J. Gardella, and H. Juppner Tuberoinfundibular Peptide 39 Binds to the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor, but Functions as an Antagonist Endocrinology, February 1, 2001; 142(2): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, P. H. Carter, and T. J. Gardella Autoactivation of Type-1 Parathyroid Hormone Receptors Containing a Tethered Ligand J. Biol. Chem., June 23, 2000; 275(26): 19456 - 19460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Mouledous, C. M. Topham, H. Mazarguil, and J.-C. Meunier Direct Identification of a Peptide Binding Region in the Opioid Receptor-like 1 Receptor by Photoaffinity Labeling with [Bpa10,Tyr14]Nociceptin J. Biol. Chem., September 15, 2000; 275(38): 29268 - 29274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Gensure, T. J. Gardella, and H. Juppner Multiple Sites of Contact between the Carboxyl-terminal Binding Domain of PTHrP-(1-36) Analogs and the Amino-terminal Extracellular Domain of the PTH/PTHrP Receptor Identified by Photoaffinity Cross-linking J. Biol. Chem., July 27, 2001; 276(31): 28650 - 28658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shimizu, J. Guo, and T. J. Gardella Parathyroid Hormone (PTH)-(1-14) and -(1-11) Analogs Conformationally Constrained by alpha -Aminoisobutyric Acid Mediate Full Agonist Responses via the Juxtamembrane Region of the PTH-1 Receptor J. Biol. Chem., December 21, 2001; 276(52): 49003 - 49012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, J. T. Potts Jr., and T. J. Gardella Minimization of Parathyroid Hormone. NOVEL AMINO-TERMINAL PARATHYROID HORMONE FRAGMENTS WITH ENHANCED POTENCY IN ACTIVATING THE TYPE-1 PARATHYROID HORMONE RECEPTOR J. Biol. Chem., July 14, 2000; 275(29): 21836 - 21843. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |