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TitleTrapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10257, Year 2024
Publish dateNov 26, 2024
AuthorsShanti Pal Gangwar / Maria V Yelshanskaya / Muhammed Aktolun / Laura Y Yen / Thomas P Newton / Kristian Strømgaard / Maria G Kurnikova / Alexander I Sobolevsky /
PubMed AbstractKainate 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 ...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.
External linksNat Commun / PubMed:39592599 / PubMed Central
MethodsEM (single particle)
Resolution2.81 - 3.75 Å
Structure data

47295

9dxq

EMDB-47295, PDB-9dxq:
Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Philanthotoxin-74
Method: EM (single particle) / Resolution: 2.81 Å

47296

9dxr

EMDB-47296, PDB-9dxr:
Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Nephilatoxin-8
Method: EM (single particle) / Resolution: 3.1 Å

47297

9dxs

EMDB-47297, PDB-9dxs:
Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Spermine
Method: EM (single particle) / Resolution: 3.55 Å

47298

9dxt

EMDB-47298, PDB-9dxt:
Ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with positive allosteric modulator BPAM-344 and channel blocker Kukoamine-A
Method: EM (single particle) / Resolution: 3.75 Å

Chemicals

ChemComp-2J9:
4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-NA:
Unknown entry

ChemComp-CL:
Unknown entry

PDB-1bdr:
HIV-1 (2: 31, 33-37) PROTEASE COMPLEXED WITH INHIBITOR SB203386

PDB-1bds:
DETERMINATION OF THE THREE-DIMENSIONAL SOLUTION STRUCTURE OF THE ANTIHYPERTENSIVE AND ANTIVIRAL PROTEIN BDS-I FROM THE SEA ANEMONE ANEMONIA SULCATA. A STUDY USING NUCLEAR MAGNETIC RESONANCE AND HYBRID DISTANCE GEOMETRY-DYNAMICAL SIMULATED ANNEALING

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-SPM:
SPERMINE

ChemComp-AH2:
1-deoxy-alpha-D-mannopyranose

PDB-1bdt:
WILD TYPE GENE-REGULATING PROTEIN ARC/DNA COMPLEX

Source
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / Kainate receptor / GluK2 / Positive allosteric modulator / BPAM344 / Channel blocker / Philanthotoxin-74 / Nephilatoxin-8 / Spermine / Kukoamine-A

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