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Structure-based design of stabilized recombinant influenza neuraminidase tetramers.
Ellis, Daniel; Lederhofer, Julia; Acton, Oliver J; Tsybovsky, Yaroslav; Kephart, Sally; Yap, Christina; Gillespie, Rebecca A; Creanga, Adrian; Olshefsky, Audrey; Stephens, Tyler; Pettie, Deleah; Murphy, Michael; Sydeman, Claire; Ahlrichs, Maggie; Chan, Sidney; Borst, Andrew J; Park, Young-Jun; Lee, Kelly K; Graham, Barney S; Veesler, David; King, Neil P; Kanekiyo, Masaru.
Afiliação
  • Ellis D; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Lederhofer J; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Acton OJ; Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195, USA.
  • Tsybovsky Y; Icosavax Inc., Seattle, WA, 98102, USA.
  • Kephart S; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Yap C; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Gillespie RA; Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, 21702, USA.
  • Creanga A; Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA.
  • Olshefsky A; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Stephens T; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Pettie D; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Murphy M; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Sydeman C; Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.
  • Ahlrichs M; Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD, 21702, USA.
  • Chan S; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Borst AJ; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Park YJ; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Lee KK; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • Graham BS; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Veesler D; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
  • King NP; Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA.
  • Kanekiyo M; Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.
Nat Commun ; 13(1): 1825, 2022 04 05.
Article em En | MEDLINE | ID: mdl-35383176
ABSTRACT
Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Orthomyxoviridae / Proteínas Virais / Neuraminidase Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Orthomyxoviridae / Proteínas Virais / Neuraminidase Idioma: En Ano de publicação: 2022 Tipo de documento: Article