6HCC

STRUCTURE OF GLUA2 LIGAND-BINDING DOMAIN (S1S2J-N775S) IN COMPLEX WITH GLUTAMATE AND TDPAM02 AT 1.6 A RESOLUTION.

Summary for 6HCC

• Entry DOI: 10.2210/pdb6hcc/pdb
• Descriptor: Glutamate receptor 2, 6,6'-(ETHANE-1,2-DIYL)BIS(4-CYCLOPROPYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE 1,1-DIOXIDE), GLUTAMIC ACID, ... (9 entities in total)
• Functional Keywords: ampa receptor, glua2, ligand-binding domain, glua2-s1s2j-n775s, membrane protein, signaling protein, positive allosteric modulator
• Biological source: Rattus norvegicus (Norway Rat); More
• Total number of polymer chains: 2
• Total formula weight: 60952.02

Authors

Laulumaa, S.,Hansen, K.V.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2018-08-14, release date: 2019-04-03, Last modification date: 2024-10-23)

Primary citation

Laulumaa, S.,Hansen, K.V.,Masternak, M.,Drapier, T.,Francotte, P.,Pirotte, B.,Frydenvang, K.,Kastrup, J.S.
Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor.
Acs Med.Chem.Lett., 10:243-247, 2019

PubMed Abstract: The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator.

PubMed: 30891120
DOI: 10.1021/acsmedchemlett.8b00369

Experimental method

X-RAY DIFFRACTION (1.617 Å)