Journal article
Investigating GIPR (Ant)Agonism: A Structural Analysis of GIP and Its Receptor
The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that is actively being targeted for its regulatory role of glycemia and energy balance. Rational design of ligands, however, has been tedious with no structural data of the GIP receptor available. This study investigates structure and function of the GIP receptor (GIPR), using a homology model based on the GLP-1 receptor.
Molecular dynamics combined with in vitro mutational data were used to pinpoint residues that play a role in ligand binding and/or receptor activation. Significant differences in binding mode were identified for the naturally occurring agonists GIP(1-30)NH2 and GIP(1-42) compared to high potency antagonists GIP(3-30)NH2 and GIP(5-30)NH2.
Residues R1832.60, R1902.67 and R3005.40 are shown to play a key role in the activation of the GIPR and evidence suggests that a disruption of the K293ECL2 – E362ECL3 salt bridge by GIPR antagonists strongly reduces GIPR activation. These findings improve the basis for rational design of ligands targeting the GIPR.
Language: | English |
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Year: | 2021 |
Pages: | 679-693.e6 |
ISSN: | 18784186 and 09692126 |
Types: | Journal article |
DOI: | 10.1016/j.str.2021.04.001 |
ORCIDs: | 0000-0002-9749-2720 , 0000-0003-0785-3762 , Nørskov, Amalie , 0000-0001-6098-058X , Qvortrup, Katrine , 0000-0002-9682-8245 and 0000-0001-9600-3254 |
Class B GIP GIPR GPCR antagonism incretin molecular dynamics mutation structural analysis truncation
Binding Sites COMPLEX DEPENDENT INSULINOTROPIC POLYPEPTIDE DYNAMICS FAMILY FRAGMENT GASTRIC-INHIBITORY POLYPEPTIDE GLP-1 RECEPTOR GLP1R protein, human GLUCAGON GLUCOSE Gastric Inhibitory Polypeptide Glucagon-Like Peptide-1 Receptor Humans Hydrogen Bonding LESSONS Models, Molecular Molecular Dynamics Simulation Mutation Protein Conformation Receptors, Gastrointestinal Hormone Structural Homology, Protein class B gastric inhibitory polypeptide receptor