4why

Structure of the Hepatitis C virus envelope glycoprotein E2 antigenic region 412-423 bound to the broadly neutralizing antibody 3/11, P21 crystal form

spinqualitylabelsall models 4why, resolution 2.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4why is a 12 chain structure with sequence from Hepacivirus C and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9WJJ4_9HEPC Publication Abstract from PubMed Neutralizing antibodies (nAbs) targeting glycoprotein E2 are important to control hepatitis C virus (HCV) infection. One conserved antigenic site (amino acids 412-423) is disordered in the reported E2 structure, but a synthetic peptide mimicking this site forms a beta-hairpin in complex with three independent nAbs. Our structure of the same peptide in complex with nAb 3/11 demonstrates a strikingly different extended conformation. We also show that residues 412-423 are essential for virus entry, but not for E2 folding. Together with the neutralizing capacity of the 3/11 Fab this indicates an unexpected structural flexibility within this epitope. NAbs 3/11 and AP33 (recognizing the extended and beta-hairpin conformation, respectively) display similar neutralizing activity despite converse binding kinetics. Our results suggest that HCV utilizes conformational flexibility as immune evasion strategy contributing to the limited immunogenicity of this epitope in patients, similar to the conformational flexibility described for other enveloped and non-enveloped viruses. IMPORTANCE: Approximately 180 million people worldwide are infected with Hepatitis C virus (HCV) and neutralizing antibodies play an important role in controlling replication of this major human pathogen. We show here that one of the most conserved antigenic sites within the major glycoprotein E2 (amino acids 412-423) - that is disordered in the recently reported crystal structure of an E2 core fragment - can adopt different conformations in the context of the infectious virus particle. Recombinant Fab fragments recognizing different conformations of this antigenic site have similar neutralization activity in spite of converse kinetic binding parameters. Of note, an antibody response targeting this antigenic region is less frequent than to other more immunogenic regions in E2. Our results suggest that the observed conformational flexibility in this conserved antigenic region contributes to the evasion of the humoral host immune response, facilitating chronicity and viral spread of HCV within an infected individual. Structural Flexibility of a Conserved Broadly Neutralizing Epitope in Hepatitis C Virus Glycoprotein E2.,Meola A, Tarr AW, England P, Meredith LW, McClure CP, Foung SK, McKeating JA, Ball JK, Rey FA, Krey T J Virol. 2014 Dec 3. pii: JVI.02190-14. PMID:25473061 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Antibody 3D structures 3D structures of non-human antibody

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