L840R substitution rearranges TLR7 interface interactions with UNC93B1. (A) Complex structure of TLR7 with UNC93B1. TLR7 is shown in coral, and UNC93B1 is depicted in blue. The large ring-shaped LRR domain is positioned on the luminal side of the membrane. TLR7 interacts with UNC93B1 through the leucine-rich repeat C-terminal (LRR-CT) motif, the luminal juxtamembrane region, and the transmembrane (TM) helix. (B) Representation of the residue 840 in both wild-type and mutant TLR7–UNC93B1 complex. (C) Heatmaps showing the contact frequency between the juxtamembrane region of TLR7 and the transmembrane helices of UNC93B1, calculated from MD simulations. Values are given in the plot to highlight the most significant differences that are boxed. In the mutant, R840 of TLR7 forms an additional contact with R157 of UNC93B1. The overall nonpolar contacts at the interface are moderately increased for the mutant at the L840R mutation site.