7wvl
From Proteopedia
Structure of P4A2 Fab in complex with Spike-RBD from SARS-CoV-2
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 emergence of new variants of SARS-CoV-2 necessitates unremitting efforts to discover novel therapeutic monoclonal antibodies (mAbs). Here, we report an extremely potent mAb named P4A2 that can neutralize all the circulating variants of concern (VOCs) with high efficiency, including the highly transmissible Omicron. The crystal structure of the P4A2 Fab:RBD complex revealed that the residues of the RBD that interact with P4A2 are a part of the ACE2-receptor-binding motif and are not mutated in any of the VOCs. The pan coronavirus pseudotyped neutralization assay confirmed that the P4A2 mAb is specific for SARS-CoV-2 and its VOCs. Passive administration of P4A2 to K18-hACE2 transgenic mice conferred protection, both prophylactically and therapeutically, against challenge with VOCs. Overall, our data shows that, the P4A2 mAb has immense therapeutic potential to neutralize the current circulating VOCs. Due to the overlap between the P4A2 epitope and ACE2 binding site on spike-RBD, P4A2 may also be highly effective against a number of future variants. A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern.,Parray HA, Narayanan N, Garg S, Rizvi ZA, Shrivastava T, Kushwaha S, Singh J, Murugavelu P, Anantharaj A, Mehdi F, Raj N, Singh S, Dandotiya J, Lukose A, Jamwal D, Kumar S, Chiranjivi AK, Dhyani S, Mishra N, Kumar S, Jakhar K, Sonar S, Panchal AK, Tripathy MR, Chowdhury SR, Ahmed S, Samal S, Mani S, Bhattacharyya S, Das S, Sinha S, Luthra K, Batra G, Sehgal D, Medigeshi GR, Sharma C, Awasthi A, Garg PK, Nair DT, Kumar R PLoS Pathog. 2022 Dec 12;18(12):e1010994. doi: 10.1371/journal.ppat.1010994. , eCollection 2022 Dec. PMID:36508467[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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