8zrd
From Proteopedia
The complex structure of SARS-CoV-2 RBD and llama single-domain antibody S4
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 PubMedSARS-CoV-2 and its variants continue to pose a significant threat to public health. Nanobodies (Nbs) that inhibit the interaction between the receptor-binding domain (RBD) of the spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2) are promising drug candidates. In this study, we report the discovery and structural characterization of a potent Nb that targets the RBD. By screening a phage display alpaca naive Nbs library using the RBD as bait, we identified sixteen candidate Nbs. Of these, nine exhibited nanomolar to micromolar binding affinity and strong neutralizing activity against pseudotyped SARS-CoV-2 viruses, with NbS4 showing the highest neutralization potency. The crystal structure of the SARS-CoV-2 RBD in complex with NbS4 revealed that this Nb binds to a site partially overlapping the ACE2 binding region. Importantly, the key binding residues of NbS4 in the RBD are conserved across most known variants, making it a promising candidate for COVID-19 treatment. Identification of a potent SARS-CoV-2 neutralizing nanobody targeting the receptor-binding domain of the spike protein.,Liu C, Hadiatullah H, Yuchi Z Int J Biol Macromol. 2024 Nov;281(Pt 2):136403. doi: , 10.1016/j.ijbiomac.2024.136403. Epub 2024 Oct 9. PMID:39383917[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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