5HK2

Human sigma-1 receptor bound to 4-IBP

5HK2 の概要

• エントリーDOI: 10.2210/pdb5hk2/pdb
• 分子名称: Sigma non-opioid intracellular receptor 1, N-(1-benzylpiperidin-4-yl)-4-iodobenzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: sigma-1 receptor, transmembrane receptor, ligand, trimer, membrane protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus inner membrane : Q99720
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 81253.03

構造登録者

Schmidt, H.R.,Zheng, S.,Gurpinar, E.G.,Koehl, A.,Manglik, A.,Kruse, A.C. (登録日: 2016-01-13, 公開日: 2016-04-06, 最終更新日: 2023-09-27)

主引用文献

Schmidt, H.R.,Zheng, S.,Gurpinar, E.,Koehl, A.,Manglik, A.,Kruse, A.C.
Crystal structure of the human sigma 1 receptor.
Nature, 532:527-530, 2016

PubMed Abstract: The human σ1 receptor is an enigmatic endoplasmic-reticulum-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain. Recently, an additional connection to amyotrophic lateral sclerosis has emerged from studies of human genetics and mouse models. Unlike many transmembrane receptors that belong to large, extensively studied families such as G-protein-coupled receptors or ligand-gated ion channels, the σ1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the σ1 receptor and its regulation by drug-like compounds remain poorly defined. Here we report crystal structures of the human σ1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the endoplasmic reticulum membrane in cells. This domain includes a cupin-like β-barrel with the ligand-binding site buried at its centre. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein.

PubMed: 27042935
DOI: 10.1038/nature17391

実験手法

X-RAY DIFFRACTION (3.2 Å)