5KZN

Metabotropic Glutamate Receptor

Summary for 5KZN

• Entry DOI: 10.2210/pdb5kzn/pdb
• Related: 5kzq
• Descriptor: Metabotropic glutamate receptor 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: mglur2, antagonist, antidepressent, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 63777.28

Authors

Chappell, M.D.,Li, R.,Smith, S.C.,Dressman, B.A.,Tromiczak, E.G.,Tripp, A.E.,Blanco, M.-J.,Vetman, T.,Quimby, S.J.,Matt, J.,Britton, T.,Fivush, A.M.,Schkeryantz, J.M.,Mayhugh, D.,Erickson, J.A.,Bures, M.,Jaramillo, C.,Carpintero, M.,de Diego, J.E.,Barberis, M.,Garcia-Cerrada, S.,Soriano, J.F.,Antonysamy, S.,Atwell, S.,MacEwan, I.,Condon, B.,Bradley, C.,Wang, J.,Zhang, A.,Conners, K.,Groshong, C.,Wasserman, S.R.,Koss, J.W.,Witkin, J.M.,Li, X.,Overshiner, C.,Wafford, K.A.,Seidel, W.,Wang, X.-S.,Heinz, B.A.,Swanson, S.,Catlow, J.,Bedwell, D.,Monn, J.A.,Mitch, C.H.,Ornstein, P. (deposition date: 2016-07-25, release date: 2016-12-28, Last modification date: 2020-07-29)

Primary citation

Chappell, M.D.,Li, R.,Smith, S.C.,Dressman, B.A.,Tromiczak, E.G.,Tripp, A.E.,Blanco, M.J.,Vetman, T.,Quimby, S.J.,Matt, J.,Britton, T.C.,Fivush, A.M.,Schkeryantz, J.M.,Mayhugh, D.,Erickson, J.A.,Bures, M.G.,Jaramillo, C.,Carpintero, M.,Diego, J.E.,Barberis, M.,Garcia-Cerrada, S.,Soriano, J.F.,Antonysamy, S.,Atwell, S.,MacEwan, I.,Condon, B.,Sougias, C.,Wang, J.,Zhang, A.,Conners, K.,Groshong, C.,Wasserman, S.R.,Koss, J.W.,Witkin, J.M.,Li, X.,Overshiner, C.,Wafford, K.A.,Seidel, W.,Wang, X.S.,Heinz, B.A.,Swanson, S.,Catlow, J.T.,Bedwell, D.W.,Monn, J.A.,Mitch, C.H.,Ornstein, P.L.
Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.
J. Med. Chem., 59:10974-10993, 2016

PubMed Abstract: As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu IC value.

PubMed: 28002967

Experimental method

X-RAY DIFFRACTION (2.8 Å)