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TitleAllosteric competition and inhibition in AMPA receptors.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateJun 4, 2024
AuthorsW Dylan Hale / Alejandra Montaño Romero / Cuauhtemoc U Gonzalez / Vasanthi Jayaraman / Albert Y Lau / Richard L Huganir / Edward C Twomey /
PubMed AbstractExcitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators ...Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases.
External linksNat Struct Mol Biol / PubMed:38834914
MethodsEM (single particle)
Resolution3.5 - 4.85 Å
Structure data

43275

8vj6

EMDB-43275, PDB-8vj6:
GluA2 bound to GYKI-52466 and Glutamate, Inhibited State 1
Method: EM (single particle) / Resolution: 3.5 Å

43276

8vj7

EMDB-43276, PDB-8vj7:
GluA2 bound to GYKI-52466 and Glutamate, Inhibited State 2
Method: EM (single particle) / Resolution: 4.85 Å

Chemicals

PDB-1ab5:
STRUCTURE OF CHEY MUTANT F14N, V21T

ChemComp-GLU:
GLUTAMIC ACID

Source
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN/INHIBITOR / ligand gated ion channel / ionotropic glutamate receptor / allosteric inhibition / MEMBRANE PROTEIN / MEMBRANE PROTEIN-INHIBITOR complex

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