7ur4
From Proteopedia
Cryo-EM Structure of the Neutralizing Antibody MPV467 in Complex with Prefusion Human Metapneumovirus F Glycoprotein
Structural highlights
FunctionFUS_HMPVC Inactive precursor that is cleaved to give rise to the mature F1 and F2 fusion glycoproteins.[UniProtKB:P03420] Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the coiled coil regions 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 cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs at the plasma or endosomal membrane. The trimer of F1-F2 (F protein) also facilitates the attachment to host cell by binding to host heparan sulfate.[UniProtKB:P03420] Major determinant of the species specificity of RSV infection (By similarity). The trimer of F1-F2 (F protein) also facilitates the attachment to host cell by binding to host heparan sulfate (PubMed:22238303).[UniProtKB:P03420][1] Publication Abstract from PubMedHuman metapneumovirus (hMPV) is a leading cause of morbidity and hospitalization among children worldwide, however, no vaccines or therapeutics are currently available for hMPV disease prevention and treatment. The hMPV fusion (F) protein is the sole target of neutralizing antibodies. To map the immunodominant epitopes on the hMPV F protein, we isolated a panel of human monoclonal antibodies (mAbs), and the mAbs were assessed for binding avidity, neutralization potency, and epitope specificity. We found the majority of the mAbs target diverse epitopes on the hMPV F protein, and we discovered multiple mAb binding approaches for antigenic site III. The most potent mAb, MPV467, which had picomolar potency, was examined in prophylactic and therapeutic mouse challenge studies, and MPV467 limited virus replication in mouse lungs when administered 24 h before or 72 h after viral infection. We determined the structure of MPV467 in complex with the hMPV F protein using cryo-electron microscopy to a resolution of 3.3 A, which revealed a complex novel prefusion-specific epitope overlapping antigenic sites II and V on a single protomer. Overall, our data reveal insights into the immunodominant antigenic epitopes on the hMPV F protein, identify a mAb therapy for hMPV F disease prevention and treatment, and provide the discovery of a prefusion-specific epitope on the hMPV F protein. Structural basis for ultrapotent antibody-mediated neutralization of human metapneumovirus.,Banerjee A, Huang J, Rush SA, Murray J, Gingerich AD, Royer F, Hsieh CL, Tripp RA, McLellan JS, Mousa JJ Proc Natl Acad Sci U S A. 2022 Jun 21;119(25):e2203326119. doi: , 10.1073/pnas.2203326119. Epub 2022 Jun 13. PMID:35696580[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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