Crystal structure of human glycine receptor-[alpha]3 bound to antagonist strychnine

• Autores: Xin Huang, Hao Chen, Klaus Michelsen, Stephen Schneider, Paul L. Shaffer
• Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 526, Nº 7572, 2015, págs. 277-280
• Idioma: inglés
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• Resumen

  • 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 activation1-8. Yet the mechanism of inactivation by antagonists remains unknown. Here we present a 3.0 Å X-ray structure of the human glycine receptor-[alpha]3 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.