Structures of the extracellular regions of the group II/III metabotropic glutamate receptors

Abstract

Metabotropic glutamate receptors play major roles in the activation of excitatory synapses in the central nerve system. We determined the crystal structure of the entire extracellular region of the group II receptor and that of the ligand-binding region of the group III receptor. A comparison among groups I, II, and III provides the structural basis that could account for the discrimination of groupspecific agonists. Furthermore, the structure of group II includes the cysteine-rich domain, which is tightly linked to the ligand-binding domain by a disulfide bridge, suggesting a potential role in transmitting a ligand-induced conformational change into the downstream transmembrane region. The structure also reveals the lateral interaction between the two cysteine-rich domains, which could stimulate clustering of the dimeric receptors on the cell surface. We propose a general activation mechanism of the dimeric receptor coupled with both ligand-binding and interprotomer rearrangements.crystallization ͉ cysteine-rich region ͉ ligand binding ͉ G protein-coupled receptor

Binding of glutamate to the umami receptor

“…X-Ray crystallographic studies of the ligand binding region of some mGluRs with and without bound glutamate show that these domains can exist in both "open" and "closed" conformations [4][5][6]. In the unliganded form, both of these domains are in an open conformation; ligand binding stabilizes a "closed-open/active" state [4].…”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…Besides its obvious structural role to anchor the receptor in the membrane, the 7TM domain contains binding sites for allosteric modulators (Dorée et al 2014;Wu et al 2014) and for the G-protein (Pin et al 1994). The extracellular N terminal contains a large structure called the BVenus flytrap domain^, first described for GABA B receptors (Galvez et al 1999) ,which contains the orthosteric ligand binding site (Kunishima et al 2000;Muto et al 2007;Tsuchiya et al 2002). The Venus flytrap domain is connected to the 7TM domain by a rigid cysteine-rich linker that communicates orthosteric ligand binding to receptor activation (Muto et al 2007).…”

“…The extracellular N terminal contains a large structure called the BVenus flytrap domain^, first described for GABA B receptors (Galvez et al 1999) ,which contains the orthosteric ligand binding site (Kunishima et al 2000;Muto et al 2007;Tsuchiya et al 2002). The Venus flytrap domain is connected to the 7TM domain by a rigid cysteine-rich linker that communicates orthosteric ligand binding to receptor activation (Muto et al 2007). After the seventh transmembrane segment, the 7TM domain gives way to a large intracellular C-terminal domain.…”

Recent Progress on the Identification of Metabotropic Glutamate 4 Receptor Ligands and Their Potential Utility as CNS Therapeutics

“…When dosed ip at 10 mg/ kg (aqueous 10% Tween-80), 20 showed >3 μM maximum concentration (C max ) in brain with a reported brain to plasma ratio (B/P) of ∼10 (as measured by total concentrationÀtime area (AUC 1À8 h)). Following the initial publication, the group at Vanderbilt evaluated the ability of VU0361737 (19) to reverse haloperidol-induced catalepsy, a preclinical rodent model of motor impairments associated with PD. In this model, rats are administered haloperidol, a dopamine D 2 antagonist which induces severe catalepsy, and then latency to withdrawal is evaluated at four doses (3, 10, 30, and 56.6 mg/kg).…”

“…Found typically as dimers, they contain two distinct regions; the classical seven transmembrane domain, ubiquitous among the GPCRs, along with a large extracellular N-terminus ( Figure 2). 19 This extracellular domain of the mGluR contains the endogenous ligand binding site, formed by two hinged globular domains, typically referred to as the Venus Flytrap domain (VFD). 20 Once glutamate binds, it causes the two domains to close, providing the required structural transformation that triggers intracellular G-protein activation.…”