Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.
Department of Protein Technologies, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.
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.
Cys 环受体家族的神经递质门控离子通道是神经系统中快速神经传递的重要介质，与许多神经疾病有关。原核和真核 Cys 环受体的现有 X 射线结构为激动剂结合、随后离子通道打开以及通道激活机制提供了巨大的见解。然而，拮抗剂失活的机制仍然未知。在这里，我们展示了人类甘氨酸受体-α3 同源五聚体与高亲和力、高特异性拮抗剂士的宁复合物的 3.0 Å X 射线结构。我们的结构使我们能够详细探索拮抗剂的分子识别。与以前的结构比较揭示了 Cys 环受体拮抗剂诱导失活的机制，涉及细胞外域的正位结合位点的扩展，该扩展与跨膜域中离子孔的关闭相关。
