Possible endogenous agonist mechanism for the activation of secretin family G protein-coupled receptors

Molecular Pharmacology
Maoqing DongLaurence J Miller

Abstract

The class B family of G protein-coupled receptors contains several potentially important drug targets, yet our understanding of the molecular basis of ligand binding and receptor activation remains incomplete. Although a key role is recognized for the cysteine-rich, disulfide-bonded amino-terminal domain of these receptors, detailed insights into ligand docking and resultant conformational changes are not clear. We postulate that binding natural ligands to this domain results in a conformational change that exposes an endogenous ligand which interacts with the body of the receptor to activate it. In this work, we examined whether a synthetic peptide corresponding to a candidate region between the first and third conserved cysteines could act as an agonist. Indeed, this peptide was a weakly potent but fully efficacious agonist, stimulating a concentration-dependent cAMP response in secretin receptor-bearing cells. This effect was maintained as the peptide length was reduced from 30 to 5, and ultimately, three residues focused on the conserved residue Asp49. The agonist potency was enhanced by cyclization through a diaminopropionic acid linker and by amino-terminal fatty acid acylation. Both ends of the cyclic peptide were shown ...Continue Reading

References

Sep 27, 1994·Proceedings of the National Academy of Sciences of the United States of America·S NystedtJ Sundelin
Jun 1, 1996·Trends in Pharmacological Sciences·T W Schwartz, M M Rosenkilde
Jul 4, 1998·The Journal of Biological Chemistry·T H JiI Ji
Aug 5, 2000·Science·K PalczewskiM Miyano
Oct 18, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·D Li, D L Elbert
Mar 9, 2004·Trends in Biochemical Sciences·Gilbert VassartSabine Costagliola
Aug 25, 2004·Proceedings of the National Academy of Sciences of the United States of America·Christy R R GraceRoland Riek
Jan 25, 2005·The Journal of Biological Chemistry·Cayle S LisenbeeLaurence J Miller

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Citations

Nov 1, 2012·ACS Combinatorial Science·Yangmei LiRichard A Houghten
Jun 6, 2012·Experimental Diabetes Research·Francis S Willard, Kyle W Sloop
Apr 25, 2006·Molecular Pharmacology·Martin Beinborn
Feb 1, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sarah O K MakBilly K C Chow
Sep 29, 2011·British Journal of Pharmacology·Dan Donnelly
Aug 26, 2011·British Journal of Pharmacology·M WheatleyJ Barwell
Sep 19, 2008·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Dimitri E GrigoriadisJohn A Williams
Feb 22, 2008·The Journal of Biological Chemistry·Steffen RungeRainer Rudolph
Dec 17, 2008·Annals of the New York Academy of Sciences·Laurence J Miller
Jan 30, 2013·Biochemical Society Transactions·James BarwellDavid R Poyner
Jul 30, 2017·Biochimica Et Biophysica Acta. Biomembranes·M Seraj UddinJeffrey M Becker
May 4, 2011·Journal of the American Chemical Society·Christian DevignyFelix Hausch
Dec 27, 2008·Pharmacology & Therapeutics·Louise Dickson, Keith Finlayson

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