Structure Summary mmCIF Format (Header) Legacy PDB Format Legacy PDB Format (Header) PDBx/mmCIF Format PDBx/mmCIF Format (gz) BinaryCIF Format (gz) Legacy PDB Format Legacy PDB Format (gz) PDBML/XML Format (gz) Structure Factors (CIF) Structure Factors (CIF - gz) Validation Full (PDF - gz) Validation (XML - gz) Validation (CIF - gz) Validation 2fo-fc coefficients (CIF - gz) Validation fo-fc coefficients (CIF - gz) Biological Assembly 1 (CIF - gz) Biological Assembly 2 (CIF - gz) Biological Assembly 1 (PDB - gz) Biological Assembly 2 (PDB - gz) Neutralizing antibody to murine norovirus PDB DOI: https://doi.org/10.2210/pdb4NCC/pdb Classification: IMMUNE SYSTEM Organism(s): Mus musculus Mutation(s): No Deposited: 2013-10-24 Released: 2014-02-19 Deposition Author(s): Smith, T. , Li, M. Experimental Data Snapshot Method: X-RAY DIFFRACTION Resolution: 2.49 Å R-Value Free: 0.273 (Depositor), 0.273 (DCC) R-Value Work: 0.204 (Depositor), 0.206 (DCC) R-Value Observed: 0.207 (Depositor) wwPDB Validation 3D Report Full Report &nbspDownload Mendeley Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization. (2014) J Virol 88 : 4543-4557

PubMed: 24501415 Search on PubMed Search on PubMed Central DOI: https://doi.org/10.1128/JVI.03685-13 Primary Citation Related Structures: 4NCC PubMed Abstract: New human norovirus strains emerge every 2 to 3 years, partly due to mutations in the viral capsid that allow escape from antibody neutralization and herd immunity. To understand how noroviruses evolve antibody resistance, we investigated the structural basis for the escape of murine norovirus (MNV) from antibody neutralization. To identify specific residues in the MNV-1 protruding (P) domain of the capsid that play a role in escape from the neutralizing monoclonal antibody (MAb) A6.2, 22 recombinant MNVs were generated with amino acid substitutions in the A'B' and E'F' loops. Six mutations in the E'F' loop (V378F, A382K, A382P, A382R, D385G, and L386F) mediated escape from MAb A6.2 neutralization. To elucidate underlying structural mechanisms for these results, the atomic structure of the A6.2 Fab was determined and fitted into the previously generated pseudoatomic model of the A6.2 Fab/MNV-1 virion complex. Previously, two distinct conformations, A and B, of the atomic structures of the MNV-1 P domain were identified due to flexibility in the two P domain loops. A superior stereochemical fit of the A6.2 Fab to the A conformation of the MNV P domain was observed. Structural analysis of our observed escape mutants indicates changes toward the less-preferred B conformation of the P domain. The shift in the structural equilibrium of the P domain toward the conformation with poor structural complementarity to the antibody strongly supports a unique mechanism for antibody escape that occurs via antigen flexibility instead of direct antibody-antigen binding. Human noroviruses cause the majority of all nonbacterial gastroenteritis worldwide. New epidemic strains arise in part by mutations in the viral capsid leading to escape from antibody neutralization. Herein, we identify a series of point mutations in a norovirus capsid that mediate escape from antibody neutralization and determine the structure of a neutralizing antibody. Fitting of the antibody structure into the virion/antibody complex identifies two conformations of the antibody binding domain of the viral capsid: one with a superior fit and the other with an inferior fit to the antibody. These data suggest a unique mode of antibody neutralization. In contrast to other viruses that largely escape antibody neutralization through direct disruption of the antibody-virus interface, we identify mutations that acted indirectly by limiting the conformation of the antibody binding loop in the viral capsid and drive the antibody binding domain into the conformation unable to be bound by the antibody. &nbspView More New human norovirus strains emerge every 2 to 3 years, partly due to mutations in the viral capsid that allow escape from antibody neutralization and herd immunity. To understand how noroviruses evolve antibody resistance, we investigated the structural basis for the escape of murine norovirus (MNV) from antibody neutralization. To identify specific residues in the MNV-1 protruding (P) domain of the capsid that play a role in escape from the neutralizing monoclonal antibody (MAb) A6.2, 22 recombinant MNVs were generated with amino acid substitutions in the A'B' and E'F' loops. Six mutations in the E'F' loop (V378F, A382K, A382P, A382R, D385G, and L386F) mediated escape from MAb A6.2 neutralization. To elucidate underlying structural mechanisms for these results, the atomic structure of the A6.2 Fab was determined and fitted into the previously generated pseudoatomic model of the A6.2 Fab/MNV-1 virion complex. Previously, two distinct conformations, A and B, of the atomic structures of the MNV-1 P domain were identified due to flexibility in the two P domain loops. A superior stereochemical fit of the A6.2 Fab to the A conformation of the MNV P domain was observed. Structural analysis of our observed escape mutants indicates changes toward the less-preferred B conformation of the P domain. The shift in the structural equilibrium of the P domain toward the conformation with poor structural complementarity to the antibody strongly supports a unique mechanism for antibody escape that occurs via antigen flexibility instead of direct antibody-antigen binding. Human noroviruses cause the majority of all nonbacterial gastroenteritis worldwide. New epidemic strains arise in part by mutations in the viral capsid leading to escape from antibody neutralization. Herein, we identify a series of point mutations in a norovirus capsid that mediate escape from antibody neutralization and determine the structure of a neutralizing antibody. Fitting of the antibody structure into the virion/antibody complex identifies two conformations of the antibody binding domain of the viral capsid: one with a superior fit and the other with an inferior fit to the antibody. These data suggest a unique mode of antibody neutralization. In contrast to other viruses that largely escape antibody neutralization through direct disruption of the antibody-virus interface, we identify mutations that acted indirectly by limiting the conformation of the antibody binding loop in the viral capsid and drive the antibody binding domain into the conformation unable to be bound by the antibody. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA. Explore in 3D : Structure | Sequence Annotations | Electron Density | Validation Report Biological Assembly 1 Explore in 3D : Structure | Sequence Annotations | Electron Density | Validation Report Biological assembly 1 assigned by authors and generated by PISA (software) Biological Assembly 2 Explore in 3D : Structure | Sequence Annotations | Electron Density | Validation Report Biological assembly 2 assigned by authors and generated by PISA (software) Macromolecule Content Total Structure Weight: 93.69 kDa Atom Count: 6,930 Modeled Residue Count: 861 Deposited Residue Count: 864 Unique protein chains: 2 Experimental Data & Validation Experimental Data Method: X-RAY DIFFRACTION Resolution: 2.49 Å R-Value Free: 0.273 (Depositor), 0.273 (DCC) R-Value Work: 0.204 (Depositor), 0.206 (DCC) R-Value Observed: 0.207 (Depositor) Structure Validation View Full Validation Report Deposition Data Released Date: 2014-02-19 Revision History (Full details and data files) Version 1.0: 2014-02-19 Type: Initial release Version 1.1: 2014-04-09 Changes: Database references Version 1.2: 2024-10-30 Changes: Data collection, Database references, Structure summary Usage & Privacy RCSB PDB is hosted by RCSB PDB is a member of Nucleic Acid Knowledgebase RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute , National Institute of Allergy and Infectious Diseases , and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729. 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