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Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation.
Sponholtz, Madeline R; Byrne, Patrick O; Lee, Alison G; Ramamohan, Ajit R; Goldsmith, Jory A; McCool, Ryan S; Zhou, Ling; Johnson, Nicole V; Hsieh, Ching-Lin; Connors, Megan; Karthigeyan, Krithika P; Crooks, Chelsea M; Fuller, Adelaide S; Campbell, John D; Permar, Sallie R; Maynard, Jennifer A; Yu, Dong; Bottomley, Matthew J; McLellan, Jason S.
Afiliación
  • Sponholtz MR; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Byrne PO; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Lee AG; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Ramamohan AR; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Goldsmith JA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • McCool RS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Zhou L; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Johnson NV; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Hsieh CL; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
  • Connors M; Division of Infectious Diseases, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
  • Karthigeyan KP; Division of Infectious Diseases, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
  • Crooks CM; Division of Infectious Diseases, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
  • Fuller AS; Division of Infectious Diseases, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
  • Campbell JD; Dynavax Technologies Corporation, Emeryville, CA 94608.
  • Permar SR; Division of Infectious Diseases, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065.
  • Maynard JA; Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712.
  • Yu D; Dynavax Technologies Corporation, Emeryville, CA 94608.
  • Bottomley MJ; Dynavax Technologies Corporation, Emeryville, CA 94608.
  • McLellan JS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712.
Proc Natl Acad Sci U S A ; 121(37): e2404250121, 2024 Sep 10.
Article en En | MEDLINE | ID: mdl-39231203
ABSTRACT
Human cytomegalovirus (HCMV) glycoprotein B (gB) is a class III membrane fusion protein required for viral entry. HCMV vaccine candidates containing gB have demonstrated moderate clinical efficacy, but no HCMV vaccine has been approved. Here, we used structure-based design to identify and characterize amino acid substitutions that stabilize gB in its metastable prefusion conformation. One variant containing two engineered interprotomer disulfide bonds and two cavity-filling substitutions (gB-C7), displayed increased expression and thermostability. A 2.8 Å resolution cryoelectron microscopy structure shows that gB-C7 adopts a prefusion-like conformation, revealing additional structural elements at the membrane-distal apex. Unlike previous observations for several class I viral fusion proteins, mice immunized with postfusion or prefusion-stabilized forms of soluble gB protein displayed similar neutralizing antibody titers, here specifically against an HCMV laboratory strain on fibroblasts. Collectively, these results identify initial strategies to stabilize class III viral fusion proteins and provide tools to probe gB-directed antibody responses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas del Envoltorio Viral / Citomegalovirus Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas del Envoltorio Viral / Citomegalovirus Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos