8fa1

Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with N969K mutation

spinqualitylabelsall models 8fa1, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fa1 is a 6 chain structure with sequence from Nostoc punctiforme PCC 73102 and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.51Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function B2J981_NOSP7 A0A8B6RKS7_SARS2 Publication Abstract from PubMed The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that one of these mutations, N969K induces a substantial displacement in the structure of the heptad repeat 2 (HR2) backbone in the HR1HR2 postfusion bundle. Due to this mutation, fusion-entry peptide inhibitors based on the Wuhan strain sequence are less efficacious. Here, we report an Omicron-specific peptide inhibitor designed based on the structure of the Omicron HR1HR2 postfusion bundle. Specifically, we inserted an additional residue in HR2 near the Omicron HR1 K969 residue to better accommodate the N969K mutation and relieve the distortion in the structure of the HR1HR2 postfusion bundle it introduced. The designed inhibitor recovers the loss of inhibition activity of the original longHR2_42 peptide with the Wuhan strain sequence against the Omicron variant in both a cell-cell fusion assay and a vesicular stomatitis virus (VSV)-SARS-CoV-2 chimera infection assay, suggesting that a similar approach could be used to combat future variants. From a mechanistic perspective, our work suggests the interactions in the extended region of HR2 may mediate the initial landing of HR2 onto HR1 during the transition of the S protein from the prehairpin intermediate to the postfusion state. Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor.,Yang K, Wang C, Kreutzberger AJB, White KI, Pfuetzner RA, Esquivies L, Kirchhausen T, Brunger AT Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2300360120. doi: , 10.1073/pnas.2300360120. Epub 2023 Mar 20. PMID:36940324 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Spike protein 3D structures

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