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From Proteopedia
MARV GP in complex with MARV16 Fab
Structural highlights
FunctionVGP_MABVM GP1 is responsible for binding to the receptor(s) on target cells. Interacts with CD209/DC-SIGN and CLEC4M/DC-SIGNR which act as cofactors for virus entry into the host cell. Binding to CD209 and CLEC4M, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses, facilitate infection of macrophages and endothelial cells. These interactions not only facilitate virus cell entry, but also allow capture of viral particles by DCs and subsequent transmission to susceptible cells without DCs infection (trans infection) (By similarity). GP2 acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in GP2, releasing the fusion hydrophobic peptide (By similarity). Publication Abstract from PubMedMarburg virus (MARV) is a filovirus that causes a severe and often lethal hemorrhagic fever(1,2). Despite the increasing frequency of MARV outbreaks, no vaccines or therapeutics are licensed for use in humans. Here, we designed mutations that improve the expression, thermostability, and immunogenicity of the prefusion MARV glycoprotein (GP) ectodomain trimer, which is the sole target of neutralizing antibodies and vaccines in development(3-8). We discovered a fully human, pan-marburgvirus monoclonal antibody, MARV16, that broadly neutralizes all MARV isolates as well as Ravn virus and Dehong virus with 40 to 100-fold increased potency relative to previously described antibodies(9). Moreover, MARV16 provides therapeutic protection in guinea pigs challenged with MARV. We determined a cryo-electron microscopy structure of MARV16-bound MARV GP showing that MARV16 recognizes a prefusion-specific epitope spanning GP1 and GP2, blocking receptor binding and preventing conformational changes required for viral entry. We further reveal the architecture of the MARV GP glycan cap, which shields the receptor binding site (RBS), underscoring architectural similarities with distantly related filovirus GPs. MARV16 and previously identified RBS-directed antibodies(9-11) can bind MARV GP simultaneously. These antibody cocktails require multiple mutations to escape neutralization by both antibodies, paving the way for MARV therapeutics resilient to viral evolution. MARV GP stabilization along with the discovery of MARV16 advance prevention and treatment options for MARV. Potent neutralization of Marburg virus by a vaccine-elicited antibody.,Addetia A, Perruzza L, Sprouse K, Park YJ, McCallum M, Stewart C, Partini B, Brown JT, Donati A, Culap K, Balmelli A, Chawla B, Kar S, Gazi M, Alfson K, Goez-Gazi Y, Carrion R Jr, Corti D, Benigni F, Veesler D Nature. 2025 Nov 12. doi: 10.1038/s41586-025-09868-1. PMID:41225006[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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