Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Abstract

Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.

Binding domain characterization of growth hormone secretagogue receptor

“…[ 42 ] Mutating F286 and F290 to alanine or polar and charged amino acids displays dramatically diminished receptor activity. [ 41 , 42 , 43 ]…”

“…[42] Mutating F286 and F290 to alanine or polar and charged amino acids displays dramatically diminished receptor activity. [41][42][43] In conclusion, GHS-R1a is capable of binding different ligands in a variety of ways, depending on the selectivity…”

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“…Very recently, the crystal structure of GHS-R1a in complex with the inverse agonist PF-5190457 ( 4 ) together with a cryo-electron microscopy structure of the Go-coupled GHS-R1a in complex with AG highlighted that the inverse agonist 4 shows a binding mode different from those of both neutral antagonists and agonists ( Figure 6 ). 20 In particular, a hydrophobic cluster and a polar network seems to be required for the receptor activation and constitutive activity.…”

“…(B) The detailed binding mode of 4 (marine blue sticks) in the orthosteric pocket of the GHS-R1a. Adapted from ref ( 20 ), which was published under a Creative Commons Attribution 4.0 International (CC BY 4.0) License.…”

Systemic infusion of exogenous ghrelin in male broiler chickens (Gallus gallus domesticus). The effect of pulse frequency, doses, and ghrelin forms on feed intake, average daily gain, corticosterone, and growth hormone concentrations

“…Additionally, ghrelin can directly affect the histaminergic system (via H1 receptors) that in turn modulates CRH release ( Taati et al, 2010 ). The GHSR-1a receptor exhibits a highly constitutive activity ( Holst et al, 2003 ; Qin et al, 2022 ). Consequently, the ability of the ghrelin receptor to retain a certain degree of activity independently of the ligand may also play a role in the differential regulation of ghrelin in feed intake.…”