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Structural and functional insight into the interaction of Clostridioides difficile toxin B and FZD7.
Kinsolving, Julia; Bous, Julien; Kozielewicz, Pawel; Kosenina, Sara; Shekhani, Rawan; Grätz, Lukas; Masuyer, Geoffrey; Wang, Yuankai; Stenmark, Pål; Dong, Min; Schulte, Gunnar.
Afiliación
  • Kinsolving J; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.
  • Bous J; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.
  • Kozielewicz P; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.
  • Kosenina S; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Shekhani R; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.
  • Grätz L; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden.
  • Masuyer G; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Wang Y; Department of Urology, Boston Children's Hospital, Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • Stenmark P; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  • Dong M; Department of Urology, Boston Children's Hospital, Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • Schulte G; Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, 17165 Stockholm, Sweden. Electronic address: gunnar.schulte@ki.se.
Cell Rep ; 43(2): 113727, 2024 Feb 27.
Article en En | MEDLINE | ID: mdl-38308843
ABSTRACT
The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD1,2,7, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD7, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD7. The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Compuestos de Boro / Clostridioides difficile / Infecciones por Clostridium Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Toxinas Bacterianas / Compuestos de Boro / Clostridioides difficile / Infecciones por Clostridium Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article País de afiliación: Suecia Pais de publicación: Estados Unidos