Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor
| Autor: | Thomas J. Smith, Robert C. Orchard, Arthur S. Kim, Ya Nan Dai, Craig B. Wilen, Christopher A. Nelson, Leon L. Hsieh, Roderick A. Stegeman, Daved H. Fremont, Herbert W. Virgin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lithocholic acid Viral protein medicine.drug_class viruses 030106 microbiology ved/biology.organism_classification_rank.species Bile acid binding medicine.disease_cause Microbiology Protein Structure Secondary virus receptor Cell Line Bile Acids and Salts Mice 03 medical and health sciences chemistry.chemical_compound fluids and secretions Protein Domains medicine Glycochenodeoxycholic acid Animals bile acid Receptors Immunologic Protein Structure Quaternary crystallography Caliciviridae Infections Multidisciplinary Bile acid ved/biology Chemistry Virus receptor Cryoelectron Microscopy Norovirus Virion virus diseases Biological Sciences digestive system diseases 3. Good health Molecular Docking Simulation Biophysics and Computational Biology A-site 030104 developmental biology PNAS Plus Biochemistry Mutation Physical Sciences Murine norovirus |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1805797115 |
| Popis: | Significance The mechanisms of norovirus capsid interactions with host receptors and the mechanisms by which soluble cofactors augment norovirus infection are not understood. We recently identified CD300lf as a cell surface receptor for murine norovirus (MNoV) and observed that a small molecule cofactor was critical for efficient binding of virus to CD300lf. Herein we identify the bile acid GCDCA as a cofactor enhancing MNoV infection and provide a biophysical characterization of the capsid–receptor and capsid–cofactor interactions, thereby providing a structure-based understanding of how noroviruses initiate cellular infection. This work has important implications for the design of norovirus therapeutics. Murine norovirus (MNoV) is closely related to human norovirus (HNoV), an infectious agent responsible for acute gastroenteritis worldwide. Here we report the X-ray crystal structure of the dimeric MNoV VP1 protruding (P) domain in complex with its cellular receptor CD300lf. CD300lf binds the P domain with a 2:2 stoichiometry, engaging a cleft between the AB and DE loops of the P2 subdomain at a site that overlaps the epitopes of neutralizing antibodies. We also identify that bile acids are cofactors enhancing MNoV cell-binding and infectivity. Structures of CD300lf–P domain in complex with glycochenodeoxycholic acid (GCDCA) and lithocholic acid (LCA) reveal two bile acid binding sites at the P domain dimer interface distant from receptor binding sites. The structural determinants for receptor and bile acid binding are supported by numerous biophysical assays utilizing interface residue mutations. We find that the monomeric affinity of CD300lf for the P domain is low and is divalent cation dependent. We have also determined the crystal structure of CD300lf in complex with phosphocholine, revealing that MNoV engages its receptor in a manner mimicking host ligands including similar metal coordination. Docking of the cocomplex structures onto a cryo-EM–derived model of MNoV suggests that each virion can make multiple CD300lf engagements, and thus, infection may be driven by the avidity of cell surface clustered CD300lf. These studies identify multiple potential modulators of norovirus infection that may act to regulate the interaction between the viral capsid P domain and its cognate cellular receptor. |
| Databáze: | OpenAIRE |
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