7sg4 | pdb_00007sg4
Structure of SARS-CoV S protein in complex with Receptor Binding Domain antibody DH1047
Structural highlights
FunctionSPIKE_SARS May down-regulate host tetherin (BST2) by lysosomal degradation, thereby counteracting its antiviral activity.[1] Attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 and CLEC4M/DC-SIGNR receptors and internalization of the virus into the endosomes of the host cell induces conformational changes in the S glycoprotein. Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membrane fusion within endosomes.[HAMAP-Rule:MF_04099][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][4] Publication Abstract from PubMedSevere acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants D614G, B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, B.1.617.1, and B.1.617.2 by a receptor binding domain (RBD)-specific human antibody, DH1047. Prophylactic and therapeutic treatment with DH1047 was protective against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B.1.351 infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among sarbecoviruses. Thus, DH1047 is a broadly protective antibody that can prevent infection and mitigate outbreaks caused by SARS-related strains and SARS-CoV-2 variants. Our results also suggest that the conserved RBD epitope bound by DH1047 is a rational target for a universal sarbecovirus vaccine. A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice.,Martinez DR, Schafer A, Gobeil S, Li D, De la Cruz G, Parks R, Lu X, Barr M, Stalls V, Janowska K, Beaudoin E, Manne K, Mansouri K, Edwards RJ, Cronin K, Yount B, Anasti K, Montgomery SA, Tang J, Golding H, Shen S, Zhou T, Kwong PD, Graham BS, Mascola JR, Montefiori DC, Alam SM, Sempowski G, Sempowski GD, Khurana S, Wiehe K, Saunders KO, Acharya P, Haynes BF, Baric RS Sci Transl Med. 2022 Jan 26;14(629):eabj7125. doi: 10.1126/scitranslmed.abj7125. , Epub 2022 Jan 26. PMID:34726473[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
