8fhy | pdb_00008fhy
Crystal structure of the SARS-CoV-2 receptor binding domain in complex with neutralizing antibody WRAIR-5021
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 PubMedThe repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants. Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques.,Sankhala RS, Lal KG, Jensen JL, Dussupt V, Mendez-Rivera L, Bai H, Wieczorek L, Mayer SV, Zemil M, Wagner DA, Townsley SM, Hajduczki A, Chang WC, Chen WH, Donofrio GC, Jian N, King HAD, Lorang CG, Martinez EJ, Rees PA, Peterson CE, Schmidt F, Hart TJ, Duso DK, Kummer LW, Casey SP, Williams JK, Kannan S, Slike BM, Smith L, Swafford I, Thomas PV, Tran U, Currier JR, Bolton DL, Davidson E, Doranz BJ, Hatziioannou T, Bieniasz PD, Paquin-Proulx D, Reiley WW, Rolland M, Sullivan NJ, Vasan S, Collins ND, Modjarrad K, Gromowski GD, Polonis VR, Michael NL, Krebs SJ, Joyce MG Nat Commun. 2024 Jan 3;15(1):200. doi: 10.1038/s41467-023-44265-0. PMID:38172512[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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