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Structure paper

TitleModulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1659, Year 2023
Publish dateMar 25, 2023
AuthorsDanyang Zhang / Remigijus Lape / Saher A Shaikh / Bianka K Kohegyi / Jake F Watson / Ondrej Cais / Terunaga Nakagawa / Ingo H Greger /
PubMed AbstractAMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an ...AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
External linksNat Commun / PubMed:36966141 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.3 Å
Structure data

15714

8ayl

EMDB-15714, PDB-8ayl:
Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059
Method: EM (single particle) / Resolution: 3.2 Å

15716

8aym

EMDB-15716, PDB-8aym:
Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118
Method: EM (single particle) / Resolution: 3.3 Å

15717

8ayn

EMDB-15717, PDB-8ayn:
Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand LY3130481
Method: EM (single particle) / Resolution: 2.8 Å

15718

8ayo

EMDB-15718, PDB-8ayo:
Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

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

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

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

ChemComp-OIJ:
5-[2-(4-fluorophenyl)-7-(4-oxidanylpiperidin-1-yl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one

ChemComp-XVD:
6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol

ChemComp-OLR:
6-[(1~{S})-1-[1-[5-(2-hydroxyethyloxy)pyridin-2-yl]pyrazol-3-yl]ethyl]-3~{H}-1,3-benzothiazol-2-one

ChemComp-GLU:
GLUTAMIC ACID / Glutamic acid

ChemComp-CYZ:
CYCLOTHIAZIDE / Cyclothiazide

Source
  • Rattus (rat)
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission

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