9DXQ

Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Philanthotoxin-74

This is a non-PDB format compatible entry.

Summary for 9DXQ

• Entry DOI: 10.2210/pdb9dxq/pdb
• EMDB information: 47295
• Descriptor: Glutamate receptor ionotropic, kainate 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: kainate receptor, gluk2, positive allosteric modulator, bpam344, channel blocker, philanthotoxin-74, membrane protein
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 4
• Total formula weight: 430950.67

Authors

Gangwar, S.P.,Yen, L.Y.,Newton, T.P.,Yelshanskaya, M.V.,Sobolevsky, A.I. (deposition date: 2024-10-11, release date: 2024-12-11)

Primary citation

Gangwar, S.P.,Yelshanskaya, M.V.,Aktolun, M.,Yen, L.Y.,Newton, T.P.,Stromgaard, K.,Kurnikova, M.G.,Sobolevsky, A.I.
Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels.
Nat Commun, 15:10257-10257, 2024

PubMed Abstract: Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge. Here, we present closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. We find that blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. Our structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies.

PubMed: 39592599
DOI: 10.1038/s41467-024-54538-x

Experimental method

ELECTRON MICROSCOPY (2.81 Å)