Viral capsid structural assembly governs the reovirus binding interface to NgR1

Understanding the mechanisms underlying viral entry is crucial for controlling viral diseases. In this study, we investigated the interactions between reovirus and Nogo-receptor 1 (NgR1), a key mediator of reovirus entry into the host central nervous system. NgR1 exhibits a unique bivalent interaction with the reovirus capsid, specifically binding at the interface between adjacent heterohexamers arranged in a precise structural pattern on the curved virus surface. Using single-molecule techniques, we explored for the first time how the capsid molecular architecture and receptor polymorphism influence virus binding. We compared the binding affinities of human and mouse NgR1 to reovirus μ1/σ3 proteins in their isolated form, self-assembled in 2D capsid patches, and within the native 3D viral topology. Our results underscore the essential role of the concave side of NgR1 and emphasize that the spatial organization and curvature of the virus are critical determinants of the stability of the reovirus-NgR1 complex. This study highlights the importance of characterizing interactions in physiologically relevant spatial configurations, providing precise insights into virus-host interactions and opening new avenues for therapeutic interventions against viral infections.