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. Author manuscript; available in PMC: 2024 Apr 1.
Published in final edited form as: Curr Opin Virol. 2023 Mar 2;59:101305. doi: 10.1016/j.coviro.2023.101305

Figure 1. Molecular and structural flavivirology.

Figure 1.

(A) Genome organization of the flavivirus genome. Flaviviral RNA is composed of a 5′UTR, one single open reading frame, and a 3′UTR. Translation of the flavivirus genomes produces a single polyprotein, later cleaved to structural and non-structural proteins by both host (in yellow) and viral NS2B-3 (in black) proteases. Capsid protein (C protein), pre-membrane protein (prM protein), and envelope protein (E protein) are structural proteins, whereas the remaining (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are non-structural proteins (B) Diagrammatic representation of the membrane topology of the flaviviral polyprotein, as well as the polyprotein cleavage sites. NS2A, NS2B, NS4A, and NS4B contain transmembrane domains, while NS1 contains conserved residues that interact with the ER membrane [19]. NS5 is indirectly associated with the ER membrane through binding to NS3, which is in turn bound to transmembrane proteins NS2A, NS4A, and NS4B [124]. (C) Respective solved protein structures predicted models, and their structural organization in the ER membrane are illustrated. Each structure is annotated with a representative PDB ID, where appropriate, and visualized in cartoon. AlphaFold 2 (AF2) was used to predict the structures for NS2A, NS4A, and NS4B transmembrane proteins as they remain unresolved. NS1 (PDB: 4O6B) consists of a homodimer, annotated as NS1/A and NS1/B. The diagram is rotated 90 degrees to depict NS1 interaction with the membrane. NS2B-NS3 protease (NS3pro) interacts with E60 (2-sulfanylidene-1,3-thiazolidin-4-one) (PDB: 6L50). NS2B-3, NS4A, 2k peptide and NS4B were predicted with high confidence by AF2 (pLDDT score > 70). NS2B anchors the NS2B-3 complex to the ER membrane. While NS4A has been predicted with high confidence, the structural organization within the membrane appears to differ from the literature, with the C-terminus of AF2-predicted NS4A residing in the ER lumen. NS5 (PDB: 5DTO) consists of an N-terminal MTase and a C-terminal RNA-dependent RNA polymerase (RdRp). Figures were created with Biorender.