Alon Assaf, Schmidt Hayden, Zheng Sanduo, Kruse Andrew C
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Adv Exp Med Biol. 2017;964:5-13. doi: 10.1007/978-3-319-50174-1_2.
The sigma-1 receptor is an enigmatic ER-resident transmembrane protein linked to a variety of human diseases. Although the receptor was first cloned 20 years ago, the molecular structure of the protein and the mechanistic basis for its interaction with drug-like small molecules have remained unclear until recently. The determination of the first crystal structure of human sigma-1 offered the first detailed views of the sigma-1 architecture, and revealed an unusual overall fold with a single transmembrane helix in each protomer. The structure shows an overall trimeric receptor arrangement, and each protomer binds a single ligand molecule at the center of its carboxy-terminal domain. These results offer detailed molecular views of receptor structure, oligomerization, and ligand recognition, providing a framework for the next era of sigma-1 research.
σ-1受体是一种神秘的内质网驻留跨膜蛋白，与多种人类疾病相关。尽管该受体在20年前首次被克隆，但直到最近，其分子结构以及与类药物小分子相互作用的机制基础仍不清楚。人σ-1受体首个晶体结构的测定提供了该受体结构的首个详细视图，揭示了一种不寻常的整体折叠，每个原体中有一个跨膜螺旋。该结构显示出受体整体呈三聚体排列，且每个原体在其羧基末端结构域的中心结合一个配体分子。这些结果提供了受体结构、寡聚化和配体识别的详细分子视图，为σ-1研究的新时代提供了一个框架。
