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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

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Related Experiment Video

Updated: Jul 8, 2025

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

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Published on: August 16, 2018

Allosteric Competition and Inhibition in AMPA Receptors.

W Dylan Hale^1,2, Alejandra Montaño Romero^1,2, Cuauhtemoc U Gonzalez^3,4

¹Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD USA.

Biorxiv : the Preprint Server for Biology

|December 11, 2023

Summary

Negative allosteric modulators, like GYKI-52466, inhibit alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) by decoupling glutamate binding from channel opening. This mechanism offers new therapeutic strategies for neurological disorders.

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Last Updated: Jul 8, 2025

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Published on: August 16, 2018

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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

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Published on: February 20, 2018

Area of Science:

Neuroscience
Molecular pharmacology
Structural biology

Background:

Excitatory neurotransmission relies on AMPA-subtype ionotropic glutamate receptors (AMPARs).
AMPAR dysregulation is implicated in numerous neurological disorders.
The precise inhibitory mechanisms of negative allosteric modulators (NAMs) on AMPARs remain incompletely understood.

Approach:

Utilized cryo-electron microscopy to capture AMPARs bound to glutamate and the NAM GYKI-52466.
Dissected the structural basis of non-competitive inhibition by GYKI-52466.
Investigated the allosteric competition between NAMs and positive allosteric modulators (PAMs).

Key Points:

Non-competitive inhibition by GYKI-52466 desensitizes AMPARs and prevents PAM potentiation.
GYKI-52466 binds to the transmembrane collar, decoupling ligand binding from channel gating.
Negative allosteric modulation by GYKI-52466 overrides positive allosteric modulation.

Conclusions:

Established a structural framework for understanding AMPAR allosteric modulation.
Provided insights into the mechanism of non-competitive AMPAR inhibition.
Laid the groundwork for rational drug design targeting AMPARs for neurological diseases.