3j7g | pdb_00003j7g
Electron cryo-microscopy of human papillomavirus 16 and H16.V5 Fab fragments
Structural highlights
FunctionVL1_HPV16 Forms an icosahedral capsid with a T=7 symmetry and a 50 nm diameter. The capsid is composed of 72 pentamers linked to each other by disulfide bonds and associated with L2 proteins. Binds to heparan sulfate proteoglycans on cell surface of basal layer keratinocytes to provide initial virion attachment. This binding mediates a conformational change in the virus capsid that facilitates efficient infection. The virion enters the host cell via endocytosis. During virus trafficking, L1 protein dissociates from the viral DNA and the genomic DNA is released to the host nucleus. The virion assembly takes place within the cell nucleus. Encapsulates the genomic DNA together with protein L2.[HAMAP-Rule:MF_04002][1] [2] [3] Publication Abstract from PubMedHuman papillomavirus 16 (HPV16) is a worldwide health threat and an etiologic agent of cervical cancer. To understand the antigenic properties of HPV16 we pursued a structural study to elucidate HPV capsids and antibody interactions. The cryo-EM structures of HPV16 mature and an altered capsid particles were solved individually and as complexes with fragment of antibody (Fab) from the neutralizing antibody H16.V5. Fitted crystal structures provided a pseudo-atomic model of the virus-Fab complex, which identified a precise footprint of H16.V5, including previously unrecognized residues. The altered capsid-Fab complex map showed that binding of the Fab induced significant conformational changes than were seen in the altered capsid structure alone. These changes included more ordered surface loops, consolidated invading arm structures, and tighter inter-capsomeric connections at the capsid floor. The H16.V5 Fab preferentially bound hexavalent capsomers likely with a stabilizing effect that directly correlated with the number of bound Fabs. Additional cryoEM reconstructions of the virus-Fab complex for different incubation times and structural analysis provide a model for a hyper-stabilization of the capsomer by H16.V5 Fab and showed that the Fab distinguishes subtle differences between antigenic sites. IMPORTANCE: Our analysis of the cryoEM reconstructions of the HPV16 capsids and virus-Fab complexes has identified the entire HPV.V5 conformational epitope and demonstrated a detailed neutralization mechanism of this clinically important monoclonal antibody against HPV16. The Fab bound and ordered the apical loops of HPV16. This conformational change was transmitted to the lower region of the capsomer resulting in enhanced inter-capsomeric interactions evidenced by the more ordered capsid floor and 'invading arm' structures. This study advances the understanding of the neutralization mechanism used by H16.V5. A CryoEM study identifies the complete H16.V5 epitope and reveals global conformational changes initiated by binding of the neutralizing antibody fragment.,Lee H, Brendle SA, Bywaters SM, Guan J, Ashley RE, Yoder JD, Makhov AM, Conway JF, Christensen ND, Hafenstein S J Virol. 2014 Nov 12. pii: JVI.02898-14. PMID:25392224[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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