|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 273, Issue 23, 14146-14151, June 5, 1998
From the Department of Medicine and Center for
Gastroenterology Research on Absorptive and Secretory Processes, Tupper
Research Institute, New England Medical Center, Tufts University School
of Medicine, Boston, Massachusetts 02111
The development of non-peptide agonists for
peptide hormone receptors would markedly expand the treatment options
for a large number of diseases. However, difficulty in identifying
non-peptide molecules which possess intrinsic activity has been a major
obstacle in achieving this goal. At present, most of the known
non-peptide ligands for peptide hormone receptors appear in standard
functional assays to be antagonists. Here, we report that a
constitutively active mutant of the human cholecystokinin-B/gastrin
receptor, Leu325
Minor Modifications of a Cholecystokinin-B/Gastrin Receptor
Non-peptide Antagonist Confer a Broad Spectrum of Functional
Properties
Glu, offers the potential to
detect even trace agonist activity of ligands which, at the wild type
receptor isoform, appear to lack efficacy. The enhanced functional
sensitivity of the mutant receptor enabled us to detect intrinsic
activity of L-365,260, an established non-peptide antagonist for the
cholecystokinin-B/gastrin receptor. Extending from this observation, we
were able to demonstrate that minor structural modifications could
convert L-365,260 into either: (i) an agonist or (ii) an inverse
agonist (attenuates ligand-independent signaling). The ability to
confer functional activity to small non-peptide ligands suggests that
the properties of endogenous peptide hormones can be mimicked, and even
extended, by considerably less complex molecules.
Copyright © 1998 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:
|
|
 |
|
  G. Liu, J.-P. Fortin, M. Beinborn, and A. S. Kopin Four Missense Mutations in the Ghrelin Receptor Result in Distinct Pharmacological Abnormalities J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1036 - 1043. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Paillasse, C. Deraeve, P. de Medina, L. Mhamdi, G. Favre, M. Poirot, and S. Silvente-Poirot Insights into the Cholecystokinin 2 Receptor Binding Site and Processes of Activation Mol. Pharmacol., December 1, 2006; 70(6): 1935 - 1945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Mukherjee, E. W. McBride, M. Beinborn, K. Dunlap, and A. S. Kopin Point Mutations in Either Subunit of the GABAB Receptor Confer Constitutive Activity to the Heterodimer Mol. Pharmacol., October 1, 2006; 70(4): 1406 - 1413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dufresne, C. Seva, and D. Fourmy Cholecystokinin and gastrin receptors. Physiol Rev, July 1, 2006; 86(3): 805 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Foucaud, I. G. Tikhonova, I. Langer, C. Escrieut, M. Dufresne, C. Seva, B. Maigret, and D. Fourmy Partial Agonism, Neutral Antagonism, and Inverse Agonism at the Human Wild-Type and Constitutively Active Cholecystokinin-2 Receptors Mol. Pharmacol., March 1, 2006; 69(3): 680 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chao, K. L. Ives, E. Goluszko, A. A. Kolokoltsov, R. A. Davey, C. M. Townsend Jr., and M. R. Hellmich Src Regulates Constitutive Internalization and Rapid Resensitization of a Cholecystokinin 2 Receptor Splice Variant J. Biol. Chem., September 30, 2005; 280(39): 33368 - 33373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Beinborn, Y. Ren, M. Blaker, C. Chen, and A. S. Kopin Ligand Function at Constitutively Active Receptor Mutants Is Affected by Two Distinct Yet Interacting Mechanisms Mol. Pharmacol., March 1, 2004; 65(3): 753 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kenakin Efficacy as a Vector: the Relative Prevalence and Paucity of Inverse Agonism Mol. Pharmacol., January 1, 2004; 65(1): 2 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Kopin, E. W. McBride, C. Chen, R. M. Freidinger, D. Chen, C.-M. Zhao, and M. Beinborn Identification of a series of CCK-2 receptor nonpeptide agonists: Sensitivity to stereochemistry and a receptor point mutation PNAS, April 29, 2003; 100(9): 5525 - 5530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kanno, G. LeSage, S. Glaser, and G. Alpini Regulation of cholangiocyte bicarbonate secretion Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G612 - G625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bläker, Y. Ren, L. Seshadri, E. W. McBride, M. Beinborn, and A. S. Kopin CCK-B/Gastrin Receptor Transmembrane Domain Mutations Selectively Alter Synthetic Agonist Efficacy without Affecting the Activity of Endogenous Peptides Mol. Pharmacol., August 1, 2000; 58(2): 399 - 406. [Abstract] [Full Text]
|
|
|
|
|
|
M. Bläker, Y. Ren, M. C. Gordon, J. E. Hsu, M. Beinborn, and A. S. Kopin Mutations within the Cholecystokinin-B/Gastrin Receptor Ligand `Pocket' Interconvert the Functions of Nonpeptide Agonists and Antagonists Mol. Pharmacol., November 1, 1998; 54(5): 857 - 863. [Abstract] [Full Text]
|
|
|
|
|
|
K. Schaffer, E. W. McBride, M. Beinborn, and A. S. Kopin Interspecies Polymorphisms Confer Constitutive Activity to the Mastomys Cholecystokinin-B/Gastrin Receptor J. Biol. Chem., October 30, 1998; 273(44): 28779 - 28784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Tibaduiza, C. Chen, and M. Beinborn A Small Molecule Ligand of the Glucagon-like Peptide 1 Receptor Targets Its Amino-terminal Hormone Binding Domain J. Biol. Chem., October 5, 2001; 276(41): 37787 - 37793. [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 |