Fig. 1. EEEV and SFV use distinct binding modes to recognize VLDLR.

a Constructs used to map alphavirus receptor LDLR class A (LA) repeat binding preferences. LDLRAD3 is a VEEV receptor⁸. VLDLR N- and C-termini are indicated. LBD ligand-binding domain. b Summary of results obtained when GFP-expressing reporter virus particles (RVPs) for the indicated alphaviruses were used to infect K562 cells expressing the receptor constructs shown in (a), with entry quantified using flow cytometry. See Supplementary Fig. 1 for additional information. “Entry” indicates that the specified construct mediates statistically significantly higher (p < 0.05) RVP infection than the control ΔLBD construct. c Top (left panel) and side (right panel) views of the cryo-EM structure of the EEEV spike protein bound to VLDLR_LBD-Fc. The spike protein is shown in surface representation and LA repeats are shown as ribbon diagrams. E2 residues K156 and R157 are shown in yellow. Ca²⁺ ions are shown as green spheres. d Ribbon diagram and cryo-EM density of the EEEV spike protein bound to VLDLR_LBD-Fc with an isolated view of a single protomer. e Top (left panel) and side (right panel) views of the cryo-EM structure of the SFV spike protein bound to VLDLR_LBD-Fc. E1 residues K345 and K347 are shown in yellow. f Ribbon diagram and cryo-EM density of the SFV spike protein bound to VLDLR_LBD-Fc with an isolated view of a single protomer. In (d, f), E2 domains (A, B, and C) and E1 domains (DI–III) and the β-ribbon connector (E2-β) are indicated. Dashed lines indicate the position of the viral membrane. The associated capsid protomer is also shown.