Faculty, Staff and Student Publications

Publication Date

11-1-2024

Journal

Nature Structural & Molecular Biology

Abstract

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.

Keywords

Receptors, AMPA, Cryoelectron Microscopy, Allosteric Regulation, Benzothiadiazines, Humans, Animals, Glutamic Acid, Models, Molecular, Protein Binding, Binding Sites, Benzodiazepines, Oxazines

DOI

10.1038/s41594-024-01328-0

PMID

38834914

PMCID

PMC11563869

PubMedCentral® Posted Date

6-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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