Crystal structure of the human σ1 receptor

Hayden R. Schmidt, Sanduo Zheng, Esin Gurpinar, Antoine Koehl, Aashish Manglik, Andrew C. Kruse
2016 Nature  
The human σ 1 receptor is an enigmatic ER-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain 1 . Recently, an additional connection to amyotrophic lateral sclerosis (ALS) has emerged from studies of human genetics and mouse models 2 . Unlike many transmembrane receptors that belong to large, extensively studied families such as G protein-coupled receptors or ligand-gated ion channels, the σ 1 receptor is an evolutionary
more » ... 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 σ 1 receptor and its regulation by drug-like compounds remain poorly defined. Here, we report crystal structures of the human σ 1 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 ER membrane in cells. This domain includes a cupin-like β-barrel with the ligandbinding site buried at its center. 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. The development of radiolabeled opiates in the 1960s and 1970s led to the discovery that the effects of these drugs are mediated by specific receptor sites with discrete pharmacological properties 3 . These receptors were divided into four classes based their ligand binding
doi:10.1038/nature17391 pmid:27042935 pmcid:PMC5550834 fatcat:jnwwasfn6nfnrft6ni2fxvhymm