The many faces of the Sigma-1 Receptor: Pathogenic variants reveal the structural determinants of ligand recognition and oligomeric interface organization

Abstract

The Sigma-1 receptor (S1R) is a ligand-regulated membrane protein whose pathogenic variants are associated with motor-neuron and neurodegenerative disorders, yet its ligand conformational selectivity and receptor organization remain incompletely understood. We systematically characterized 35 pathogenic or likely pathogenic human SIGMAR1 variants, comprising 24 missense substitutions, six single-residue deletions, and five truncations, using an integrated computational framework to combine structural modeling, stability prediction, binding-pocket characterization, molecular docking, protein-ligand interaction profiling, comparative structural pharmacology, and inter-subunit interface analysis. Resveratrol was employed as a non-canonical molecular probe to challenge the structural tolerance of the S1R ligand-binding cavity. Missense variants largely preserved the global receptor fold and canonical binding pocket despite heterogeneous predicted stability and local interaction remodeling, whereas single-residue deletions produced greater model-dependent structural heterogeneity. Premature truncations progressively disrupted the native binding architecture and inter-subunit organization. Resveratrol showed robust predicted accommodation in wild-type and most missense receptors, while substantial truncation of the C-terminal domain markedly impaired standard recognition. Comparative analysis of predicted S1R–ligand interactions showed that resveratrol shared more structural interaction features with established S1R agonists than with antagonists, although this trend was not statistically significant and does not establish agonist activity. Inter-subunit analysis further revealed that preservation of monomeric receptor architecture does not necessarily imply preservation of specific oligomeric interactions. Together, these findings define a structural continuum of pathogenic S1R perturbation, from locally altered but ligand-compatible receptors to extensively remodeled variants lacking the architecture required for canonical ligand recognition and receptor assembly. The results provide testable structural hypotheses for variant-dependent S1R dysfunction and for direct experimental evaluation of resveratrol-S1R recognition.