PDBsum entry 5cnj

Signaling protein

PDB id: 5cnj

Contents

Protein chains

445 a.a.

Ligands

NAG

52Q ×2

Waters ×147

PDB id:

5cnj

Name:

Signaling protein

Title:

Mglur2 with glutamate analog

Structure:

Metabotropic glutamate receptor 2. Chain: a, b. Fragment: unp residues 2-493. Synonym: mglur2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grm2, gprc1b, mglur2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.65Å R-factor: 0.195 R-free: 0.241

Authors:

J.A.Monn,D.K.Clawson

Key ref:

J.A.Monn et al. (2015). Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist. J Med Chem, 58, 7526-7548. PubMed id: 26313429 DOI: 10.1021/acs.jmedchem.5b01124

Date:

17-Jul-15 Release date: 09-Sep-15

Protein chains

Q14416  (GRM2_HUMAN) -  Metabotropic glutamate receptor 2 from Homo sapiens

Seq: 872 a.a.

Struc: 445 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1021/acs.jmedchem.5b01124

J Med Chem 58:7526-7548 (2015)

PubMed id: 26313429

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.

J.A.Monn, L.Prieto, L.Taboada, J.Hao, M.R.Reinhard, S.S.Henry, C.D.Beadle, L.Walton, T.Man, H.Rudyk, B.Clark, D.Tupper, S.R.Baker, C.Lamas, C.Montero, A.Marcos, J.Blanco, M.Bures, D.K.Clawson, S.Atwell, F.Lu, J.Wang, M.Russell, B.A.Heinz, X.Wang, J.H.Carter, B.G.Getman, J.T.Catlow, S.Swanson, B.G.Johnson, D.B.Shaw, D.L.McKinzie.

ABSTRACT

Identification of orthosteric mGlu2/3 receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.