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

Authors: Chen, Lei  Dürr, Katharina L  Gouaux, Eric 
Citation: Chen L, etal., Science. 2014 Aug 29;345(6200):1021-6. doi: 10.1126/science.1258409. Epub 2014 Aug 7.
Pubmed: (View Article at PubMed) PMID:25103405
DOI: Full-text: DOI:10.1126/science.1258409

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.

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CRRD Object Information
CRRD ID: 13432307
Created: 2017-09-26
Species: All species
Last Modified: 2017-09-26
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.