Meng Fuhui, Xiao Yang, Ji Yujia, Sun Ziyi, Zhou Xiaoming
Department of Integrated Traditional Chinese and Western Medicine, Rare Diseases Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Nat Commun. 2022 Mar 10;13(1):1267. doi: 10.1038/s41467-022-28946-w.
The sigma-1 receptor (σR) is a non-opioid transmembrane receptor which has been implicated in many diseases, including neurodegenerative disorders and cancer. After more than forty years of research, substantial progress has been made in understanding this unique receptor, yet the molecular mechanism of its ligand entry pathway remains uncertain. Published structures of human σR reveal its homotrimeric organization of a cupin-fold β-barrel body that contains the ligand binding site, a carboxy-terminal V-shaped two-helix bundle, and a single amino-terminal transmembrane helix, while simulation studies have suggested a ligand entry pathway that is generated by conformational rearrangements of the cupin-fold domain. Here, we present multiple crystal structures, including an open-like conformation, of σR from Xenopus laevis. Together with functional binding analysis our data suggest that access to the σR ligand binding site is likely achieved by protein conformational changes that involve the carboxy-terminal two-helix bundle, rather than structural changes in the cupin-fold domain.
σ-1受体（σR）是一种非阿片类跨膜受体，与许多疾病有关，包括神经退行性疾病和癌症。经过四十多年的研究，在理解这种独特的受体方面取得了重大进展，但其配体进入途径的分子机制仍不确定。已发表的人类σR结构揭示了其由包含配体结合位点的cupin折叠β桶体、羧基末端V形双螺旋束和单个氨基末端跨膜螺旋组成的同三聚体结构，而模拟研究提出了一种由cupin折叠结构域的构象重排产生的配体进入途径。在这里，我们展示了非洲爪蟾σR的多个晶体结构，包括一种类似开放的构象。结合功能结合分析，我们的数据表明，进入σR配体结合位点可能是通过涉及羧基末端双螺旋束的蛋白质构象变化实现的，而不是cupin折叠结构域的结构变化。
