title: Crystal structure of the human σ1 receptor.
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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hayden R
authors.initials: HR
authors.lastname: Schmidt
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Sanduo
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Esin
authors.initials: E
authors.lastname: Gurpinar
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Koehl
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aashish
authors.initials: A
authors.lastname: Manglik
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
mesh_terms: D001549:Benzamides / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007425:Intracellular Membranes / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D017480:Receptors, sigma / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D000097605:Sigma-1 Receptor
chemical_list: D001549:Benzamides; D007555:Isoxazoles; D008024:Ligands; D010880:Piperidines; D011725:Pyridines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C107238:1-propyl-5-(3-p-tolylisoxazol-5-yl)-1,2,3,6-tetrahydropyridine; C088152:N-(N-benzylpiperidin-4-yl)-4-iodobenzamide