Structural dynamics of the GluK3-kainate receptor neurotransmitter binding domains revealed by cryo-EM

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…6 A ˚of GluK2 in the presence of the competitive antagonist LY466195 that was reminiscent of the closed-state structure of GluA2 (Meyerson et al, 2016). More recently, low-resolution structures of GluK3 were obtained in the presence of kainate or SYM2081 as well as competitive antagonists UBP301 and UBP310, with the latter showing significant asymmetric distortions at the ABD layer (Kumari et al, 2019(Kumari et al, , 2020. The gating mechanism of kainate receptors is unknown because neither the apo nor the open-state structures of kainate receptors have been resolved.…”

“…The gating mechanism of kainate receptors is unknown because neither the apo nor the open-state structures of kainate receptors have been resolved. When compared with the closed-state AMPA receptor structure, the putative desensitized state structures of kainate receptors predict unusually large conformational changes associated with desensitization (Meyerson et al, 2014(Meyerson et al, , 2016Kumari et al, 2019Kumari et al, , 2020. Recently, the cryo-EM structure of GluK2/5 heteromer was solved in the apo, antagonistbound, and desensitized states (Khanra et al, 2021).…”

“…These data suggest that GluK2 and GluK5 subunits of the heteromer fulfill distinct roles to bring about channel desensitization and activation, respectively. The desensitized structures of kainate receptor homomers and heteromers reveal that kainate receptors undergo unusually large conformational changes to reach the desensitized state(s) compared with AMPA receptors (Meyerson et al, 2014(Meyerson et al, , 2016Kumari et al, 2019Kumari et al, , 2020Khanra et al, 2021).…”

Kainate Receptor Antagonists: Recent Advances and Therapeutic Perspective

“…Attempts to structurally resolve the architecture of tetrameric kainate receptors have led to low-resolution structures of the GluK3 receptor in complex with kainate or the antagonists UBP301 and UBP310 [34,35], along with cryo-EM structures of the heterotetramer associated with L-Glu or the antagonist CNQX (Figure 2) [36]. This allowed the characterization of changes occurring during the activation of the kainate receptor.…”

Emerging insights into the structure and function of ionotropic glutamate delta receptors

“…However, cryo‐EM structures of full‐length GluD1 (Burada, Vinnakota, & Kumar, 2020a) and GluD2 (Burada, Vinnakota, & Kumar, 2020b) receptors revealed a distinct domain arrangement in the receptor tetramer when compared to other families of ionotropic glutamate receptors (Figure 1). Unlike AMPA (Sobolevsky, Rosconi, & Gouaux, 2009), kainate (Kumari et al, 2020; Kumari, Vinnakota, & Kumar, 2019; Meyerson et al, 2014) and NMDA (Karakas & Furukawa, 2014) receptors, where the dimer partners at the amino terminal domain and ligand binding domain layer are swapped between the distal and proximal subunits of the receptor tetramer, GluD receptors adopt a non‐swapped architecture (Figure 1). While disrupted amino terminal domain dimer‐of‐dimer interface has been observed previously in AMPA (Dürr et al, 2014; Meyerson et al, 2014; Nakagawa, Cheng, Ramm, Sheng, & Walz, 2005; Zhao, Chen, Swensen, Qian, & Gouaux, 2019) and NMDA receptors (Jalali‐Yazdi, Chowdhury, Yoshioka, & Gouaux, 2018; Zhu et al, 2016), the non‐swapped architecture is unique to GluD receptors.…”