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- PDB-7v1n: Structure of the Clade 2 C. difficile TcdB in complex with its re... -

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Basic information

Entry
Database: PDB / ID: 7v1n
TitleStructure of the Clade 2 C. difficile TcdB in complex with its receptor TFPI
Components
  • Isoform Beta of Tissue factor pathway inhibitor
  • Toxin B
KeywordsTOXIN / TcdB4 / TFPI / receptor / complex
Function / homology
Function and homology information


negative regulation of blood coagulation / Extrinsic Pathway of Fibrin Clot Formation / host cell cytosol / Transferases; Glycosyltransferases; Hexosyltransferases / endopeptidase inhibitor activity / cellular response to steroid hormone stimulus / glycosyltransferase activity / side of membrane / cysteine-type peptidase activity / host cell endosome membrane ...negative regulation of blood coagulation / Extrinsic Pathway of Fibrin Clot Formation / host cell cytosol / Transferases; Glycosyltransferases; Hexosyltransferases / endopeptidase inhibitor activity / cellular response to steroid hormone stimulus / glycosyltransferase activity / side of membrane / cysteine-type peptidase activity / host cell endosome membrane / caveola / serine-type endopeptidase inhibitor activity / blood coagulation / toxin activity / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / lipid binding / host cell plasma membrane / cell surface / endoplasmic reticulum / proteolysis / extracellular space / extracellular region / membrane / metal ion binding / plasma membrane
Similarity search - Function
Tissue factor pathway inhibitor-like / Dermonecrotic/RTX toxin, membrane localization domain / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / Membrane Localization Domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / TcdA/TcdB toxin, pore forming domain / TcdA/TcdB pore forming domain / CGT/MARTX, cysteine protease (CPD) domain ...Tissue factor pathway inhibitor-like / Dermonecrotic/RTX toxin, membrane localization domain / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / Membrane Localization Domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / TcdA/TcdB toxin, pore forming domain / TcdA/TcdB pore forming domain / CGT/MARTX, cysteine protease (CPD) domain / CGT/MARTX, cysteine protease (CPD) domain superfamily / Peptidase C80 family / CGT/MARTX cysteine protease (CPD) domain profile. / Choline-binding repeat / Putative cell wall binding repeat / Cell wall/choline-binding repeat / Cell wall-binding repeat profile. / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / Nucleotide-diphospho-sugar transferases
Similarity search - Domain/homology
Tissue factor pathway inhibitor / Toxin B
Similarity search - Component
Biological speciesClostridioides difficile (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLuo, J. / Yang, Q. / Zhang, X. / Zhang, Y. / Wan, L. / Li, Y. / Tao, L.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31970129 China
National Natural Science Foundation of China (NSFC)31800128 China
CitationJournal: Cell / Year: 2022
Title: TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile.
Authors: Jianhua Luo / Qi Yang / Xiaofeng Zhang / Yuanyuan Zhang / Li Wan / Xiechao Zhan / Yao Zhou / Liuqing He / Danyang Li / Dazhi Jin / Ying Zhen / Jing Huang / Yanyan Li / Liang Tao /
Abstract: The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, ...The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, and clade 2 strains exclusively express two TcdB variants (TcdB2 and TcdB4) that use unknown receptors distinct from the classic TcdB. Here, we performed CRISPR/Cas9 screens for TcdB4 and identified tissue factor pathway inhibitor (TFPI) as its receptor. Using cryo-EM, we determined a complex structure of the full-length TcdB4 with TFPI, defining a common receptor-binding region for TcdB. Residue variations within this region divide major TcdB variants into 2 classes: one recognizes Frizzled (FZD), and the other recognizes TFPI. TFPI is highly expressed in the intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4. These findings establish TFPI as a colonic crypt receptor for TcdB from clade 2 C. difficile and reveal new mechanisms for CDI pathogenesis.
History
DepositionAug 5, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2022Group: Database references / Structure summary / Category: citation / citation_author / struct
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _struct.title

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Structure visualization

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Assembly

Deposited unit
A: Toxin B
K: Isoform Beta of Tissue factor pathway inhibitor


Theoretical massNumber of molelcules
Total (without water)299,1362
Polymers299,1362
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1300 Å2
ΔGint-11 kcal/mol
Surface area111520 Å2

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Components

#1: Protein Toxin B


Mass: 270454.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: isoform B4 / Source: (gene. exp.) Clostridioides difficile (bacteria) / Gene: tcdB, toxB / Production host: Escherichia coli (E. coli)
References: UniProt: Q9EXR0, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Protein Isoform Beta of Tissue factor pathway inhibitor / TFPI / Extrinsic pathway inhibitor / EPI / Lipoprotein-associated coagulation inhibitor / LACI


Mass: 28681.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TFPI, LACI, TFPI1 / Production host: Homo sapiens (human) / References: UniProt: P10646
Sequence detailsThese conflicts are isoform B4 sequence.

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSourceDetails
1TFPI-TcdB4 complexCOMPLEXall0MULTIPLE SOURCES
2Toxin BCOMPLEX#11RECOMBINANTthe sequence comes from CD_8864 reference strain
3Isoform Beta of Tissue factor pathway inhibitorCOMPLEX#21RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
22Clostridioides difficile (bacteria)1496CD_8864 reference strain
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33Homo sapiens (human)9606
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 227825 / Symmetry type: POINT

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