Crystal structure of human glycine receptor-α3 bound to antagonist strychnine

Nature. 2015 Oct 8;526(7572):277-80. doi: 10.1038/nature14972. Epub 2015 Sep 28.


Neurotransmitter-gated ion channels of the Cys-loop receptor family are essential mediators of fast neurotransmission throughout the nervous system and are implicated in many neurological disorders. Available X-ray structures of prokaryotic and eukaryotic Cys-loop receptors provide tremendous insights into the binding of agonists, the subsequent opening of the ion channel, and the mechanism of channel activation. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-α3 homopentamer in complex with a high affinity, high-specificity antagonist, strychnine. Our structure allows us to explore in detail the molecular recognition of antagonists. Comparisons with previous structures reveal a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Ion Channel Gating / drug effects
  • Models, Molecular
  • Protein Multimerization / drug effects
  • Protein Structure, Tertiary / drug effects
  • Receptors, Glycine / antagonists & inhibitors
  • Receptors, Glycine / chemistry*
  • Receptors, Glycine / metabolism*
  • Strychnine / chemistry
  • Strychnine / metabolism*
  • Strychnine / pharmacology
  • Substrate Specificity


  • Receptors, Glycine
  • glycine receptor alpha3 subunit
  • Strychnine

Associated data

  • PDB/5CFB