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. 2025 May 29;188(11):2943-2956.e24.
doi: 10.1016/j.cell.2025.02.036. Epub 2025 Apr 4.

Structural basis for plasticity in receptor engagement by an encephalitic alphavirus

Saravanan Raju  1 , Sathvik Palakurty  2 , Alan Sariol  3 , Ngan Wagoner  3 , Lucas J Adams  1 , Sean Hui  1 , William B Klimstra  4 , Daved H Fremont  5 , Michael S Diamond  6
Affiliations

Structural basis for plasticity in receptor engagement by an encephalitic alphavirus

Saravanan Raju et al. Cell. .

Abstract

The structural basis for shifts in receptor usage remains poorly understood despite the implications for virus adaptation and emergence. Western equine encephalitis virus (WEEV) strains exhibit different patterns of engagement for two of their entry receptors: very-low-density lipoprotein receptor (VLDLR) and protocadherin 10 (PCDH10). Using structural and functional studies, we show that while all WEEV strains have a lipoprotein class A (LA) domain binding site near the E1 fusion loop, VLDLR engagement requires a second binding site in E2 that can vary with single nucleotide substitutions. We also resolve a structure of PCDH10 bound to WEEV, which reveals interactions near the E1 fusion loop with residues that also mediate LA domain binding. Evolutionary analysis enabled the generation of a PCDH10 decoy that protects in vivo against all WEEV strains tested. Our experiments demonstrate how viruses can engage multiple receptors using shared determinants, which likely impacts cellular tropism and virulence.

Keywords: alphavirus; cryoelectron microscopy; pathogenesis; receptor; structure; therapy.

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Conflict of interest statement

Declaration of interests M.S.D. is a consultant for Inbios, Moderna, IntegerBio, Merck, GlaxoSmithKline, Bavarian Nordic, and Akagera Medicines. The Diamond laboratory has received unrelated funding from Bavarian Nordic, Moderna, Vir Biotechnology, and IntegerBio.

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