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Structure paper

TitleModulation of GluA2-γ5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 10, Page 1481-1494, Year 2023
Publish dateAug 31, 2023
AuthorsShanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Aryeh Korman / Drew R Jones / Alexander I Sobolevsky /
PubMed AbstractSynaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat ...Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.
External linksNat Struct Mol Biol / PubMed:37653241 / PubMed Central
MethodsEM (single particle)
Resolution2.72 - 3.88 Å
Structure data

EMDB-16052, PDB-8bhf:
Cryo-EM structure of stalled rabbit 80S ribosomes in complex with human CCR4-NOT and CNOT4
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-40741, PDB-8ss2:
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
Method: EM (single particle) / Resolution: 3.58 Å

EMDB-40742, PDB-8ss3:
Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-40743, PDB-8ss4:
Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunits TARP gamma-5 and cornichon-2 (apo state)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-40744, PDB-8ss5:
Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 (apo state)
Method: EM (single particle) / Resolution: 3.56 Å

EMDB-40745, PDB-8ss6:
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK, channel blocker spermidine and antiepileptic drug perampanel (closed state)
Method: EM (single particle) / Resolution: 3.01 Å

EMDB-40746, PDB-8ss7:
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK, channel blocker spermidine and antiepileptic drug perampanel (closed state)
Method: EM (single particle) / Resolution: 2.76 Å

EMDB-40747, PDB-8ss8:
Structure of AMPA receptor GluA2 complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state)
Method: EM (single particle) / Resolution: 2.81 Å

EMDB-40748, PDB-8ss9:
Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state)
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-40749, PDB-8ssa:
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state)
Method: EM (single particle) / Resolution: 3.88 Å

EMDB-40750, PDB-8ssb:
Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state)
Method: EM (single particle) / Resolution: 3.66 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / antagonist, medication*YM

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-AJP:
Digitonin / detergent*YM

ChemComp-SPD:
SPERMIDINE

ChemComp-NA:
Unknown entry

ChemComp-6ZP:
2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile / medication*YM

ChemComp-HOH:
WATER

ChemComp-GLU:
GLUTAMIC ACID

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsRIBOSOME / translational control / mRNA decay / deadenylation / ribosome stalling / human CCR4-NOT / MEMBRANE PROTEIN / AMPA receptor / spermidine / TARP gamma-5 / cornichon-2 / SIGNALING PROTEIN / neurotransmission / Ion-channel / perampanel

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