Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
Trends Pharmacol Sci. 2012 Sep;33(9):482-93. doi: 10.1016/j.tips.2012.06.005. Epub 2012 Jul 11.
Cys loop, glutamate, and P2X receptors are ligand-gated ion channels (LGICs) with 5, 4, and 3 protomers, respectively. There is now growing atomic level understanding of their gating mechanisms. Although each family is unique in the architecture of the ligand-binding pocket, the pathway for motions to propagate from ligand-binding domain to transmembrane domain, and the gating motions of the transmembrane domain, there are common features among the LGICs, which are the focus of the present review. In particular, agonists and competitive antagonists apparently induce opposite motions of the binding pocket. A simple way to control the motional direction is ligand size. Agonists, usually small, induce closure of the binding pocket, leading to opening of the channel pore, whereas antagonists, usually large, induce opening of the binding pocket, thereby stabilizing the closed pore. A cross-family comparison of the gating mechanisms of the LGICs, focusing in particular on the role played by ligand size, provides new insight on channel activation/inhibition and design of pharmacological compounds.
Cys 环、谷氨酸和 P2X 受体分别是具有 5、4 和 3 个原体的配体门控离子通道 (LGIC)。现在对它们的门控机制有了越来越深入的原子水平的理解。尽管每个家族在配体结合口袋的结构上都是独特的，但从配体结合域到跨膜域的运动传播途径以及跨膜域的门控运动是 LGIC 共有的特征，这是本综述的重点。特别是，激动剂和竞争性拮抗剂显然会引起结合口袋的相反运动。控制运动方向的一种简单方法是配体大小。通常较小的激动剂会诱导结合口袋关闭，从而打开通道孔，而通常较大的拮抗剂会诱导结合口袋打开，从而稳定关闭的孔。对 LGIC 门控机制的跨家族比较，特别是关注配体大小所起的作用，为通道激活/抑制和药理学化合物的设计提供了新的见解。
