Common and Selective Molecular Determinants Involved in Metabotopic Glutamate Receptor Agonist Activity

Abstract

Several potent and group selective agonists of metabotropic glutamate receptors (mGluRs) have been docked at mGlu1,2,4R binding sites in the closed conformation of the bilobate extracellular domain. Quisqualic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) were selected for mGlu1R, dicarboxycyclopropylglycine (DCG-IV), LY354740, (S)-4-carboxyphenylglycine (4CPG) for mGlu2R, and (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), (S)-4-phosphonophenylglycine (PPG) for mGlu4R. The models show a conserved binding pattern for the glycine moiety (alpha-amino and alpha-acidic functions) and group specific bindings for the distal acidic function. The best agonists allow optimized interaction with both lobes of the binding domain. Interlobe connections around the ligand are also described and participate in stabilizing the closed form of the amino-terminal domain. Altogether, the docking models support the proposal that the stabilization of a closed state represents a key step in agonist activation of mGluRs.

Molecular mechanism of the sweet taste enhancers

“…The extensive nature of interlobe connections in mGluRs was also noted previously (15). Direct interlobe interactions found in the closed conformation of mGluRs manifest as both electrostatic and hydrophobic interactions in the model of T1R2.…”

Allosteric modulation of metabotropic glutamate receptors by chloride ions

“…This site is conserved in all mGluRs, except in mGlu2 where site 2 is occupied by the negatively charged carboxylate moiety of Asp146, which likely mimics Cl 2 . This carboxylate moiety makes hydrogen bonds with the NH backbone of Tyr216 and a salt bridge with Arg271, a residue involved in interlobe connections through a cation-p interaction with Tyr144 and a salt bridge with Glu273 (64), as confirmed in a recent crystal structure of mGlu2 (65). Interestingly, mGlu2 is also the least-sensitive mGluR to Cl 2 .…”

Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists

“…In the case of MAP4, the ␣-methyl group makes steric bumps with the aromatic ring of Tyr-227, whereas the third carboxylic group of ACPT-II, lying close to the carboxylic group of Asp-309, causes ionic repulsion. In contrast, when the same approach was used to dock the mGlu8 potent agonist ACPT-I, a stereoisomer of ACPT-II, the third COO Ϫ group was oriented differently at the binding site and can be accommodated well in a closed form of the binding pocket (6,20,34).…”

“…These studies revealed two major conformational changes resulting from agonist binding. A first one is the closure of at least one VFTM in the dimer, as expected from modeling studies of other family 3 GPCRs (6,(8)(9)(10)20). Indeed, glutamate binds to lobe I within the cleft that separates both lobes and also can interact with residues from lobe II leading to the stabilization of a closed state.…”

“…France). They were generated by using the coordinates of the mGlu1 VFTM closed form bound with glutamate (PDB ID code 1ewk:A) and a sequence alignment described (6,20). Glutamate and L-AP4 bioactive conformations (26) were positioned manually in the mGlu8-wt binding site according to 1ewk:A and submitted to energy minimization (Steepest Descent convergence 2 kcal͞mol͞A; Conjugate Gradient convergence 0.1 kcal͞ mol͞A) (20).…”