Rational Design of Peptidomimetics for Class B GPCRs: Potent Non-Peptide GLP-1 Receptor Agonists
The family of class B G-protein coupled receptors (GPCRs) includes cognate receptors for peptide hormones like secretin, glucagon, glucagon-like peptide-1 (GLP-1), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory polypeptide (GIP), corticotropin-releasing factor (CRF), and so on. Whereas class A GPCRs recognize much smaller ligands, such as dopamine, somatostatin, and enkephalins, by mostly using residues in transmembrane domains and extracellular loops proximal to membrane, all class B GPCRs possess significantly long N-terminal chains and large extracellular loops which constitute multiple binding pockets to host their large ligands [1,2].
All of these class B peptides play unique and critical functions in human physiology and are found to be attractive to treat many diseases . For instance, glucagon, GLP-1 and GIP are involved in glucose homeostasis and are potential novel...
KeywordsVasoactive Intestinal Peptide Extracellular Loop Gastric Inhibitory Polypeptide Pituitary Adenylate Cyclase Activate Peptide Large Extracellular Loop
The work was supported by Welch Foundation (AT-1595), American Diabetes Association (7-07-JF-02), and Texas Advanced Research Program (009741-0031-2006).
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