5MFW

Crystal structure of the GluK1 ligand-binding domain in complex with kainate and BPAM-121 at 2.10 A resolution

Summary for 5MFW

• Entry DOI: 10.2210/pdb5mfw/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 1,Glutamate receptor ionotropic, kainate 1, 7-chloro-4-(2-fluoroethyl)-2,3-dihydro-1,2,4-benzothiadiazine 1,1-dioxide, CHLORIDE ION, ... (8 entities in total)
• Functional Keywords: ionotropic glutamate receptor, gluk1 ligand-binding domain, membrane protein, positive allosteric modulator
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P22756
• Total number of polymer chains: 2
• Total formula weight: 59931.77

Authors

Larsen, A.P.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2016-11-18, release date: 2017-04-12, Last modification date: 2024-11-06)

Primary citation

Larsen, A.P.,Fievre, S.,Frydenvang, K.,Francotte, P.,Pirotte, B.,Kastrup, J.S.,Mulle, C.
Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors.
Mol. Pharmacol., 91:576-585, 2017

PubMed Abstract: Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of ()-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors have been reported, no such ligands are available for KARs. In this study, we investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. 4-cyclopropyl-7-fluoro-3,4-dihydro-2-1,2,4-benzothiadiazine 1,1-dioxide (BPAM344) potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 M), with an EC of 79 M. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. 4-cyclopropyl-7-hydroxy-3,4-dihydro-2-1,2,4-benzothiadiazine 1,1-dioxide (BPAM521) potentiated the recorded peak current amplitude of GluK2a 12-fold at a concentration of 300 M with an EC value of 159 M, whereas no potentiation of the glutamate-evoked response was observed for 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2-1,2,4-benzothiadiazine 1,1-dioxide (BPAM121) at the highest concentration of modulator tested (300 M). BPAM344 (100 M) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15-fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1 (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator-binding sites at the GluK1 dimer interface. In conclusion, this study may enable the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigation of the function of KARs in vivo and may prove useful for pharmacologically controlling the activity of neuronal networks.

PubMed: 28360094
DOI: 10.1124/mol.116.107599

Experimental method

X-RAY DIFFRACTION (2.1 Å)