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Structure paper

TitleActivation of kainate receptor GluK2-Neto2 complex.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 11, Page 2176-2184, Year 2025
Publish dateAug 22, 2025
AuthorsShanti Pal Gangwar / Maria V Yelshanskaya / Laura Y Yen / Thomas P Newton / Alexander I Sobolevsky /
PubMed AbstractKainate receptors (KARs) are tetrameric, ligand-gated ion channels of the ionotropic glutamate receptor family that mediate excitatory neurotransmission and modulate neuronal circuits and synaptic ...Kainate receptors (KARs) are tetrameric, ligand-gated ion channels of the ionotropic glutamate receptor family that mediate excitatory neurotransmission and modulate neuronal circuits and synaptic plasticity during development of the central nervous system. KARs are implicated in psychiatric and neurological diseases and represent a target of therapeutic intervention. Native KARs form complexes with neuropilin and tolloid-like auxiliary subunits (Neto1 and Neto2), which modulate their function, trafficking and synaptic localization. Here we present structures of rat GluK2 KAR in the apo closed state and in the open states activated by agonist kainate and positive allosteric modulator BPAM344, solved in the presence and absence of Neto2 using time-resolved cryo-electron microscopy. While the binding of Neto2 does not change the behavior of individual or dimeric ligand-binding domains (LBDs) or the ion channel, it prevents tightening of the interface between two LBD dimers during activation and slows the kinetics of deactivation. Our structures illuminate the mechanism of KAR activation and its modulation by Neto2.
External linksNat Struct Mol Biol / PubMed:40846810 / PubMed Central
MethodsEM (single particle)
Resolution3.22 - 4.24 Å
Structure data

EMDB-48897, PDB-9n4l:
Composite map for GluK2 in the apo state with asymmetric ligand binding domain
Method: EM (single particle) / Resolution: 4.24 Å

EMDB-48898, PDB-9n4m:
Composite map for GluK2 in the apo state with 2-fold symmetrical ligand-binding domain
Method: EM (single particle) / Resolution: 3.77 Å

EMDB-48899, PDB-9n4n:
Composite map for GluK2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Method: EM (single particle) / Resolution: 3.32 Å

EMDB-48900, PDB-9n4o:
Composite map for GluK2-0xNeto2 in the apo state with asymmetric ligand-binding domain
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-48901, PDB-9n4p:
Composite map for GluK2-1xNeto2 in the apo state
Method: EM (single particle) / Resolution: 3.58 Å

EMDB-48902, PDB-9n4q:
Composite map for GluK2-2xNeto2 in the apo state
Method: EM (single particle) / Resolution: 3.48 Å

EMDB-48903, PDB-9n4r:
Composite map for GluK2-0xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Method: EM (single particle) / Resolution: 3.48 Å

EMDB-48904, PDB-9n4s:
Composite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-48905, PDB-9n4t:
Composite map for GluK2-2xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Method: EM (single particle) / Resolution: 3.22 Å

Chemicals

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

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

ChemComp-NA:
Unknown entry

ChemComp-KAI:
3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE / neurotransmitter, agonist*YM

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

Source
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / Kainate receptor / GluK2 / Ion Channel / Neto2

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