7c8w | pdb_00007c8w
Structure of sybody MR17 in complex with the SARS-CoV-2 S receptor-binding domain (RBD)
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, the causative agent of COVID-19(1), features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein(1-6). Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics(7-17). Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 mug mL(-1)). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak. A synthetic nanobody targeting RBD protects hamsters from SARS-CoV-2 infection.,Li T, Cai H, Yao H, Zhou B, Zhang N, van Vlissingen MF, Kuiken T, Han W, GeurtsvanKessel CH, Gong Y, Zhao Y, Shen Q, Qin W, Tian XX, Peng C, Lai Y, Wang Y, Hutter CAJ, Kuo SM, Bao J, Liu C, Wang Y, Richard AS, Raoul H, Lan J, Seeger MA, Cong Y, Rockx B, Wong G, Bi Y, Lavillette D, Li D Nat Commun. 2021 Jul 30;12(1):4635. doi: 10.1038/s41467-021-24905-z. PMID:34330908[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
