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Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2.
- Source :
-
The FEBS journal [FEBS J] 2021 Feb; Vol. 288 (3), pp. 995-1007. Date of Electronic Publication: 2020 Jul 08. - Publication Year :
- 2021
-
Abstract
- Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. DATABASE: The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code https://doi.org/10.2210/pdb6RUQ/pdb. The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact).<br /> (© 2020 Federation of European Biochemical Societies.)
- Subjects :
- Allosteric Regulation
Animals
Benzodiazepines chemistry
Benzodiazepines pharmacology
Crystallography, X-Ray
Excitatory Amino Acid Antagonists chemistry
Excitatory Amino Acid Antagonists pharmacology
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Organophosphonates chemistry
Organophosphonates pharmacology
Protein Binding
Protein Domains
Quinoxalines chemistry
Quinoxalines pharmacology
Rats
Receptors, AMPA antagonists & inhibitors
Receptors, AMPA genetics
Recombinant Proteins chemistry
Sf9 Cells
Spodoptera
Benzodiazepines metabolism
Excitatory Amino Acid Antagonists metabolism
Organophosphonates metabolism
Quinoxalines metabolism
Receptors, AMPA metabolism
Recombinant Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1742-4658
- Volume :
- 288
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 32543078
- Full Text :
- https://doi.org/10.1111/febs.15455