5O4F

Structure of GluK3 ligand-binding domain (S1S2) in complex with the agonist LM-12b at 2.10 A resolution

Summary for 5O4F

• Entry DOI: 10.2210/pdb5o4f/pdb
• Descriptor: Glutamate receptor ionotropic, kainate 3, GLYCEROL, (3~{a}~{R},4~{S},6~{a}~{R})-1-methyl-4,5,6,6~{a}-tetrahydro-3~{a}~{H}-pyrrolo[3,4-c]pyrazole-3,4-dicarboxylic acid, ... (7 entities in total)
• Functional Keywords: ionotropic glutamate receptor, kainate receptor, ligand-binding domain, gluk3, glur7, agonist, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P42264
• Total number of polymer chains: 2
• Total formula weight: 59700.52

Authors

Moellerud, S.,Frydenvang, K.,Kastrup, J.S. (deposition date: 2017-05-29, release date: 2017-07-26, Last modification date: 2024-01-17)

Primary citation

Mllerud, S.,Pinto, A.,Marconi, L.,Frydenvang, K.,Thorsen, T.S.,Laulumaa, S.,Venskutonyte, R.,Winther, S.,Moral, A.M.C.,Tamborini, L.,Conti, P.,Pickering, D.S.,Kastrup, J.S.
Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors.
ACS Chem Neurosci, 8:2056-2064, 2017

PubMed Abstract: Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with K of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (K of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.

PubMed: 28691798
DOI: 10.1021/acschemneuro.7b00201

Experimental method

X-RAY DIFFRACTION (2.1 Å)