Zika virus capsid protein closed structure modulates binding to host lipid systems

Abstract Zika virus (ZIKV), a mosquito‐borne Flavivirus of international concern, causes congenital microcephaly in newborns and Guillain–Barré syndrome in adults. ZIKV capsid (C) protein, one of three key structural proteins, is essential for viral assembly and encapsidation. In dengue virus, a closely related flavivirus, the homologous C protein interacts with host lipid systems, namely intracellular lipid droplets, for successful viral replication. Here, we investigate ZIKV C interaction with host lipid systems, showing that it binds host lipid droplets but, contrary to expected, in an unspecific manner. Contrasting with other flaviviruses, ZIKV C also does not bind very‐low density‐lipoproteins. Comparing with other Flavivirus , capsid proteins show that ZIKV C structure is particularly thermostable and seems to be locked into an auto‐inhibitory conformation due to a disordered N ‐terminal, hence blocking specific interactions and supporting the experimental differences observed. Such distinct structural features must be considered when targeting capsid proteins in drug development.