Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2

Christian Krintel, Jerzy Dorosz, Andreas Haahr Larsen, Thor Seneca Thorsen, Raminta Venskutonytė, Osman Mirza, Michael Gajhede, Thomas Boesen, Jette Sandholm Jensen Kastrup

Research output: Contribution to journalArticlepeer-review

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, non-competitive (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 result 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.

Original languageEnglish
Pages (from-to)995-1007
JournalThe FEBS Journal
Volume288
Issue number3
Early online date2020 Jun 15
DOIs
Publication statusPublished - 2021

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Subject classification (UKÄ)

  • Medicinal Chemistry

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