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TitleStructural and functional insight into the interaction of Clostridioides difficile toxin B and FZD.
Journal, issue, pagesCell Rep, Vol. 43, Issue 2, Page 113727, Year 2024
Publish dateFeb 27, 2024
AuthorsJulia Kinsolving / Julien Bous / Pawel Kozielewicz / Sara Košenina / Rawan Shekhani / Lukas Grätz / Geoffrey Masuyer / Yuankai Wang / Pål Stenmark / Min Dong / Gunnar Schulte /
PubMed AbstractThe G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible ...The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD, 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 FZD, 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 FZD. 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.
External linksCell Rep / PubMed:38308843
MethodsEM (single particle)
Resolution2.89 - 3.63 Å
Structure data

EMDB-18373, PDB-8qen:
cryo-EM structure of apo Clostridioides difficile toxin B
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-18374, PDB-8qeo:
cryo-EM structure complex of Frizzled-7 and Clostridioides difficile toxin B
Method: EM (single particle) / Resolution: 3.26 Å

EMDB-18402: cryo-EM structure of apo-TcdB
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-18403: cryo-EM map of apo Clostridioides difficile toxin B
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-18409: cryo-EM structure of TcdB-FZD7
Method: EM (single particle) / Resolution: 3.63 Å

EMDB-18410: cryo-EM structure of TcdB-FZD7
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-18411: cryo-EM structure of TcdB-FZD7
Method: EM (single particle) / Resolution: 2.89 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • Priestia megaterium DSM 319 (bacteria)
  • clostridioides difficile (bacteria)
  • Spodoptera frugiperda (fall armyworm)
  • homo sapiens (human)
KeywordsTOXIN / microbiology / pore forming region / CROP dynamics / Structural Genomics / Structural Genomics Consortium / SGC / micriobiology / class F G protein-coupled receptors

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