Abstract
GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.
Highlights
G protein-coupled receptors (GPCR) represent the largest family of membrane proteins in eukaryotes
After performing a BLAST search, three crystal structures with highest sequence identity and overall sequence coverage were chosen as templates: the murine μ-opioid receptor (PDB-ID: 5C1M) in complex with an agonist, the human P2Y1R (PDB-ID: 4XNV) in complex with an allosteric antagonist, and the zebrafish lysophosphatidic acid receptor LPA6 (PDB-ID: 5XSZ) in complex with oleoyl-R-glycerol, showing sequence identities of 24.8%, 25.5% and 27.3%, respectively [28,29,30,50]
Structures of class A GPCRs belonging to the same δ-branch as GPR18 (P2Y1, LPA6) andone GPCR that is activated by a lipid like GPR18 (LPA6) were selected
Summary
G protein-coupled receptors (GPCR) represent the largest family of membrane proteins in eukaryotes. They are structurally characterized by seven transmembrane (TM) regions connected by three extracellular (ECL1-3) and three intracellular loops (ICL1-3), an extracellular N-terminal and an intracellular C-terminal domain. Upon binding of the cognate agonist (e.g., biogenic amine neurotransmitter, nucleotide, lipid, amino acid, peptide, glycoprotein) conformational changes are induced. These result in coupling with G proteins, and thereby transducing information from the extracellular to the intracellular compartment and inducing or inhibiting downstream signaling pathways [1,2]. The functionalities and roles of orphan GPCRs under
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