6ffa

FMDV Leader protease bound to substrate ISG15

spinqualitylabelsall models 6ffa, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ffa is a 2 chain structure with sequence from Foot-and-mouth disease virus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.5Å Ligands: AYE, GOL, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed In response to viral infection, cells mount a potent inflammatory response that relies on ISG15 and ubiquitin posttranslational modifications. Many viruses use deubiquitinases and deISGylases that reverse these modifications and antagonize host signaling processes. We here reveal that the leader protease, Lb(pro), from foot-and-mouth disease virus (FMDV) targets ISG15 and to a lesser extent, ubiquitin in an unprecedented manner. Unlike canonical deISGylases that hydrolyze the isopeptide linkage after the C-terminal GlyGly motif, Lb(pro) cleaves the peptide bond preceding the GlyGly motif. Consequently, the GlyGly dipeptide remains attached to the substrate Lys, and cleaved ISG15 is rendered incompetent for reconjugation. A crystal structure of Lb(pro) bound to an engineered ISG15 suicide probe revealed the molecular basis for ISG15 proteolysis. Importantly, anti-GlyGly antibodies, developed for ubiquitin proteomics, are able to detect Lb(pro) cleavage products during viral infection. This opens avenues for infection detection of FMDV based on an immutable, host-derived epitope. Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies.,Swatek KN, Aumayr M, Pruneda JN, Visser LJ, Berryman S, Kueck AF, Geurink PP, Ovaa H, van Kuppeveld FJM, Tuthill TJ, Skern T, Komander D Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2371-2376. doi:, 10.1073/pnas.1710617115. Epub 2018 Feb 20. PMID:29463763 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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