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-Structure paper
Title | Structural and functional basis of VLDLR usage by Eastern equine encephalitis virus. |
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Journal, issue, pages | Cell, Vol. 187, Issue 2, Page 360-374.e19, Year 2024 |
Publish date | Jan 18, 2024 |
Authors | Lucas J Adams / Saravanan Raju / Hongming Ma / Theron Gilliland / Douglas S Reed / William B Klimstra / Daved H Fremont / Michael S Diamond / |
PubMed Abstract | The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and ...The very-low-density lipoprotein receptor (VLDLR) comprises eight LDLR type A (LA) domains and supports entry of distantly related alphaviruses, including Eastern equine encephalitis virus (EEEV) and Semliki Forest virus (SFV). Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage more than one LA domain simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection. Whereas all EEEV strains show conservation of two VLDLR-binding sites, the EEEV PE-6 strain and a few other EEE complex members feature a single amino acid substitution that enables binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge. |
External links | Cell / PubMed:38176410 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.86 - 6.03 Å |
Structure data | EMDB-42187: Eastern equine encephalitis virus (PE-6) VLP (icosahedral) EMDB-42188, PDB-8ufa: EMDB-42189: Eastern equine encephalitis virus (PE-6) VLP in complex with full-length VLDLR (icosahedral) EMDB-42190, PDB-8ufb: EMDB-42191: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-2) (icosahedral) EMDB-42192, PDB-8ufc: EMDB-42193: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-3) (icosahedral) EMDB-42194: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-3) (asymmetric unit) EMDB-42195: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-5)[W132A] (icosahedral) EMDB-42196: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-5)[W132A] (asymmetric unit) EMDB-42197: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-6)[W132A, W210A] (icosahedral) EMDB-42198: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-6)[W132A, W210A] (asymmetric unit) EMDB-42199: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-8)[W132A, W210A, W256A] (icosahedral) EMDB-42200: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-8)[W132A, W210A, W256A] (asymmetric unit) EMDB-42201: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(3-8) (icosahedral) EMDB-42202: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-6)[W89A] (icosahedral) EMDB-42203: Eastern equine encephalitis virus (PE-6) VLP in complex with VLDLR LA(1-6)[W89A] (asymmetric unit) EMDB-42212: Eastern equine encephalitis virus (FL93-939) VLP in complex with VLDLR LA(1-6) (icosahedral) |
Chemicals | ChemComp-NAG: ChemComp-CA: |
Source |
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Keywords | VIRAL PROTEIN / virus / Structural Genomics / Center for Structural Biology of Infectious Diseases / CSBID / receptor |