X-ray structures of AMPA receptor-cone snail toxin complexes illuminate activation mechanism.

Lei Chen, Katharina L. Dürr, Eric Gouaux

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

AMPA-sensitive glutamate receptors are crucial to the structural and dynamic properties of the brain, to the development and function of the central nervous system, and to the treatment of neurological conditions from depression to cognitive impairment. However, the molecular principles underlying AMPA receptor activation have remained elusive. We determined multiple x-ray crystal structures of the GluA2 AMPA receptor in complex with a Conus striatus cone snail toxin, a positive allosteric modulator, and orthosteric agonists, at 3.8 to 4.1 angstrom resolution. We show how the toxin acts like a straightjacket on the ligand-binding domain (LBD) "gating ring," restraining the domains via both intra- and interdimer cross-links such that agonist-induced closure of the LBD "clamshells" is transduced into an irislike expansion of the gating ring. By structural analysis of activation-enhancing mutants, we show how the expansion of the LBD gating ring results in pulling forces on the M3 helices that, in turn, are coupled to ion channel gating.

Original languageEnglish (US)
Pages (from-to)1021-1026
Number of pages6
JournalScience (New York, N.Y.)
Volume345
Issue number6200
DOIs
StatePublished - Aug 29 2014

ASJC Scopus subject areas

  • General

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