The activation mechanism of class-C G-protein coupled receptors

Abstract

, either homo or heterodimers. This complex architecture raises a number of important questions. Here we will discuss our view of how agonist binding within the large ECD triggers the necessary change of conformation, or stabilize a specific conformation, of the heptahelical domain leading to G-protein activation. How ligands acting within the heptahelical domain can change the properties of these complex macromolecules.

The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids

“…These NTD residues largely correspond to secondary structure elements such as the core alpha helices in lobe 1 and the beta strands in lobe 2, as well as sites predicted to interact with bound ligand (see below and Figure 5). Overall, the NTD shows less conservation than the cysteine-rich and TM domains, consistent with these latter domains' roles in receptor structure and coupling to intracellular signaling pathways [49,50]. …”

“…It is instructive to consider this question in the context of the structure of C family GPCRs. The ligand-binding NTD of C family GPCRs is thought to adopt a conformation resembling a bilobate clamshell-like structure [49,50]. Stabilization of the closed conformation of the clamshell – through interactions between bound ligand and the inner faces of the two lobes (lobes 1 and 2) – leads to receptor activation.…”

“…Stabilization of the closed conformation of the clamshell – through interactions between bound ligand and the inner faces of the two lobes (lobes 1 and 2) – leads to receptor activation. For amino acid-binding receptors, the binding pocket formed by the two lobes of the clamshell can be divided into two regions: a proximal pocket, comprising residues that interact with the glycine moiety of the amino acid ligand (α-carboxylate, α-amino and α-proton), and a distal pocket, comprising residues that interact with the ligand's R group side chain [49]. Studies on a wide variety of amino acid-binding proteins have identified a core "signature" motif of 5 residues within the proximal binding pocket that participate in critical interactions with the amino acid ligand ([32,33]; see Figure 5).…”

“…It is unclear what role this position may play in receptor function. Based on existing models of C family GPCR structure [49,61], this site resides within or near the hinge of the ligand-binding clamshell. The apparent positive selection acting on this site may therefore indicate its importance in modulating some aspect of ligand binding or receptor activation.…”

Group I mGluRs and Long-Term Depression: Potential Roles in Addiction?

“…Thus, mGluR5-dependent control of tyrosine phosphorylation may play an important constitutive role [86]. In future studies, it will be important to determine whether the constitutive activity of mGluRs reflects altered agonist availability [6, 47], for example through nonsynaptic sources as mentioned above or whether this reflects alterations in intrinsic mGluR signaling [94].…”