8d47 | pdb_00008d47
fp.006 Fab in complex with SARS-CoV-2 Fusion Peptide
Structural highlights
FunctionSPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099][1] [2] [3] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three 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.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Publication Abstract from PubMedEmergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants. Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein.,Bianchini F, Crivelli V, Abernathy ME, Guerra C, Palus M, Muri J, Marcotte H, Piralla A, Pedotti M, De Gasparo R, Simonelli L, Matkovic M, Toscano C, Biggiogero M, Calvaruso V, Svoboda P, Cervantes Rincon T, Fava T, Podesvova L, Shanbhag AA, Celoria A, Sgrignani J, Stefanik M, Honig V, Pranclova V, Michalcikova T, Prochazka J, Guerrini G, Mehn D, Ciabattini A, Abolhassani H, Jarrossay D, Uguccioni M, Medaglini D, Pan-Hammarstrom Q, Calzolai L, Fernandez D, Baldanti F, Franzetti-Pellanda A, Garzoni C, Sedlacek R, Ruzek D, Varani L, Cavalli A, Barnes CO, Robbiani DF Sci Immunol. 2023 Mar 17;8(81):eade0958. doi: 10.1126/sciimmunol.ade0958. Epub , 2023 Mar 10. PMID:36701425[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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