| Structural highlights
Function
PG057_VACCW Major envelope protein that plays a role in the biogenesis of the viral double membrane and in egress of virus from the host cell (PubMed:17475658, PubMed:27466413, PubMed:8999886). Produces the wrapped form of virus that is required for cell-to-cell spread (PubMed:27466413, PubMed:29540596). Acts as a lipase with broad specificity including phospholipase C, phospholipase A, and triacylglycerol lipase activities (PubMed:9405398).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Mpox is a zoonotic disease endemic to Central and West Africa. Since 2022, two human-adapted monkeypox virus (MPXV) strains have caused large outbreaks outside these regions. Tecovirimat is the most widely used drug to treat mpox. It blocks viral egress by targeting the viral phospholipase F13; however, the structural details are unknown, and mutations in the F13 gene can result in resistance against tecovirimat, raising public health concerns. Here we report the structure of an F13 homodimer using X-ray crystallography, both alone (2.1 A) and in complex with tecovirimat (2.6 A). Combined with molecular dynamics simulations and dimerization assays, we show that tecovirimat acts as a molecular glue that promotes dimerization of the phospholipase. Tecovirimat resistance mutations identified in clinical MPXV isolates map to the F13 dimer interface and prevent drug-induced dimerization in solution and in cells. These findings explain how tecovirimat works, allow for better monitoring of resistant MPXV strains and pave the way for developing more potent and resilient therapeutics.
Structural insights into tecovirimat antiviral activity and poxvirus resistance.,Vernuccio R, Martinez Leon A, Poojari CS, Buchrieser J, Selverian CN, Jaleta Y, Meola A, Guivel-Benhassine F, Porrot F, Haouz A, Chevreuil M, Raynal B, Mercer J, Simon-Loriere E, Chandran K, Schwartz O, Hub JS, Guardado-Calvo P Nat Microbiol. 2025 Mar;10(3):734-748. doi: 10.1038/s41564-025-01936-6. Epub 2025 , Feb 12. PMID:39939832[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Honeychurch KM, Yang G, Jordan R, Hruby DE. The vaccinia virus F13L YPPL motif is required for efficient release of extracellular enveloped virus. J Virol. 2007 Jul;81(13):7310-5. PMID:17475658 doi:10.1128/JVI.00034-07
- ↑ Sivan G, Weisberg AS, Americo JL, Moss B. Retrograde Transport from Early Endosomes to the trans-Golgi Network Enables Membrane Wrapping and Egress of Vaccinia Virus Virions. J Virol. 2016 Sep 12;90(19):8891-905. PMID:27466413 doi:10.1128/JVI.01114-16
- ↑ Bryk P, Brewer MG, Ward BM. Vaccinia Virus Phospholipase Protein F13 Promotes Rapid Entry of Extracellular Virions into Cells. J Virol. 2018 May 14;92(11):e02154-17. PMID:29540596 doi:10.1128/JVI.02154-17
- ↑ Grosenbach DW, Ulaeto DO, Hruby DE. Palmitylation of the vaccinia virus 37-kDa major envelope antigen. Identification of a conserved acceptor motif and biological relevance. J Biol Chem. 1997 Jan 17;272(3):1956-64. PMID:8999886 doi:10.1074/jbc.272.3.1956
- ↑ Baek SH, Kwak JY, Lee SH, Lee T, Ryu SH, Uhlinger DJ, Lambeth JD. Lipase activities of p37, the major envelope protein of vaccinia virus. J Biol Chem. 1997 Dec 19;272(51):32042-9. PMID:9405398 doi:10.1074/jbc.272.51.32042
- ↑ Vernuccio R, Martínez León A, Poojari CS, Buchrieser J, Selverian CN, Jaleta Y, Meola A, Guivel-Benhassine F, Porrot F, Haouz A, Chevreuil M, Raynal B, Mercer J, Simon-Loriere E, Chandran K, Schwartz O, Hub JS, Guardado-Calvo P. Structural insights into tecovirimat antiviral activity and poxvirus resistance. Nat Microbiol. 2025 Mar;10(3):734-748. PMID:39939832 doi:10.1038/s41564-025-01936-6
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