7qti
From Proteopedia
SARS-CoV-2 S Omicron Spike B.1.1.529 - 3-P2G3 and 1-P5C3 Fabs (Global)
Structural highlights
Function[SPIKE_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][M1E1E4_9HIV1] Publication Abstract from PubMedThe SARS-CoV-2 Omicron variant has very high levels of transmission, is resistant to neutralization by authorized therapeutic human monoclonal antibodies (mAb) and is less sensitive to vaccine-mediated immunity. To provide additional therapies against Omicron, we isolated a mAb named P2G3 from a previously infected vaccinated donor and showed that it has picomolar-range neutralizing activity against Omicron BA.1, BA.1.1, BA.2 and all other variants tested. We solved the structure of P2G3 Fab in complex with the Omicron spike using cryo-electron microscopy at 3.04 A resolution to identify the P2G3 epitope as a Class 3 mAb that is different from mAb-binding spike epitopes reported previously. Using a SARS-CoV-2 Omicron monkey challenge model, we show that P2G3 alone, or in combination with P5C3 (a broadly active Class 1 mAb previously identified), confers complete prophylactic or therapeutic protection. Although we could select for SARS-CoV-2 mutants escaping neutralization by P2G3 or by P5C3 in vitro, they had low infectivity and 'escape' mutations are extremely rare in public sequence databases. We conclude that this combination of mAbs has potential as an anti-Omicron drug. Patient-derived monoclonal antibody neutralizes SARS-CoV-2 Omicron variants and confers full protection in monkeys.,Fenwick C, Turelli P, Ni D, Perez L, Lau K, Herate C, Marlin R, Lana E, Pellaton C, Raclot C, Esteves-Leuenberger L, Campos J, Farina A, Fiscalini F, Dereuddre-Bosquet N, Relouzat F, Abdelnabi R, Foo CS, Neyts J, Leyssen P, Levy Y, Pojer F, Stahlberg H, LeGrand R, Trono D, Pantaleo G Nat Microbiol. 2022 Sep;7(9):1376-1389. doi: 10.1038/s41564-022-01198-6. Epub, 2022 Jul 25. PMID:35879526[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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