Allosteric competition and inhibition in AMPA receptors.

Autor: Hale WD; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Montaño Romero A; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Gonzalez CU; Center for Membrane Biology, Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA., Jayaraman V; Center for Membrane Biology, Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA., Lau AY; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. alau@jhmi.edu., Huganir RL; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhuganir@jhmi.edu.; Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rhuganir@jhmi.edu., Twomey EC; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Twomey@jhmi.edu.; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Twomey@jhmi.edu.; The Beckman Center for Cryo-EM at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Twomey@jhmi.edu.; Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. Twomey@jhmi.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Nov; Vol. 31 (11), pp. 1669-1679. Date of Electronic Publication: 2024 Jun 04.
DOI: 10.1038/s41594-024-01328-0
Abstrakt: 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.
Competing Interests: Competing interests R.L.H. is a scientific cofounder and scientific advisory board (SAB) member of Neumora Therapeutics and an SAB member of MAZE Therapeutics. The other authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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