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- EMDB-31628: Structure of the Clade 2 C. difficile TcdB in complex with its re... -

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Basic information

Entry
Database: EMDB / ID: EMD-31628
TitleStructure of the Clade 2 C. difficile TcdB in complex with its receptor TFPI
Map data
Sample
  • Complex: TFPI-TcdB4 complex
    • Complex: Toxin B
      • Protein or peptide: Toxin B
    • Complex: Isoform Beta of Tissue factor pathway inhibitor
      • Protein or peptide: Isoform Beta of Tissue factor pathway inhibitor
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 / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / Dermonecrotic/RTX toxin, membrane localization domain / Membrane Localization Domain / TcdA/TcdB toxin, pore forming domain / TcdA/TcdB pore forming domain / CGT/MARTX, cysteine protease (CPD) domain ...Tissue factor pathway inhibitor-like / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / Dermonecrotic/RTX toxin, membrane localization domain / Membrane Localization 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)
Methodsingle 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, 2 items
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, 2021-
Header (metadata) releaseFeb 23, 2022-
Map releaseFeb 23, 2022-
UpdateMar 30, 2022-
Current statusMar 30, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7v1n
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31628.png

Downloads & links

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Map

FileDownload / File: emd_31628.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.108103745 - 0.18961984
Average (Standard dev.)2.6591724e-05 (±0.003734182)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 347.84 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0871.0871.087
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z347.840347.840347.840
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.1080.1900.000

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Supplemental data

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Sample components

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Entire : TFPI-TcdB4 complex

EntireName: TFPI-TcdB4 complex
Components
  • Complex: TFPI-TcdB4 complex
    • Complex: Toxin B
      • Protein or peptide: Toxin B
    • Complex: Isoform Beta of Tissue factor pathway inhibitor
      • Protein or peptide: Isoform Beta of Tissue factor pathway inhibitor

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Supramolecule #1: TFPI-TcdB4 complex

SupramoleculeName: TFPI-TcdB4 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Toxin B

SupramoleculeName: Toxin B / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: the sequence comes from CD_8864 reference strain
Source (natural)Organism: Clostridioides difficile (bacteria) / Strain: CD_8864 reference strain
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #3: Isoform Beta of Tissue factor pathway inhibitor

SupramoleculeName: Isoform Beta of Tissue factor pathway inhibitor / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Toxin B

MacromoleculeName: Toxin B / type: protein_or_peptide / ID: 1 / Details: isoform B4 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
Source (natural)Organism: Clostridioides difficile (bacteria)
Molecular weightTheoretical: 270.454 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSLVNRKQLE KMANVRFRVQ EDEYVAILDA LEEYHNMSEN TVVEKYLKLK DINSLTDTYI DTYKKSGRNK ALKKFKEYLV TEILELKNS NLTPVEKNLH FIWIGGQIND TAINYINQWK DVNSDYNVNV FYDSNAFLIN TLKKTIIESA SNDTLESFRE N LNDPEFNH ...String:
MSLVNRKQLE KMANVRFRVQ EDEYVAILDA LEEYHNMSEN TVVEKYLKLK DINSLTDTYI DTYKKSGRNK ALKKFKEYLV TEILELKNS NLTPVEKNLH FIWIGGQIND TAINYINQWK DVNSDYNVNV FYDSNAFLIN TLKKTIIESA SNDTLESFRE N LNDPEFNH TAFFRKRMQI IYDKQQNFIN YYKAQKEENP DLIIDDIVKT YLSNEYSKDI DELNAYIEES LNKVTENSGN DV RNFEEFK TGEVFNLYEQ ELVERWNLAG ASDILRVAIL KNIGGVYLDV DMLPGIHPDL FKDINKPDSV KTAVDWEEMQ LEA IMKYKE YIPEYTSKHF DTLDEEVQSS FESVLASKSD KSEIFLPLGD IEVSPLEVKV AFAKGSIINQ ALISAKDSYC SDLL IKQIQ NRYKILNDTL GPIISQGNDF NTTMNNFGES LGAIANEENI SFIAKIGSYL RVGFYPEANT TITLSGPTIY AGAYK DLLT FKEMSIDTSI LSSELRNFEF PKVNISQATE QEKNSLWQFN EERAKIQFEE YKKNYFEGAL GEDDNLDFSQ NTVTDK EYL LEKISSSTKS SERGYVHYIV QLQGDKISYE AACNLFAKNP YDSILFQKNI EDSEVAYYYN PTDSEIQEID KYRIPDR IS DRPKIKLTLI GHGKAEFNTD IFAGLDVDSL SSEIETIIDL AKADISPKSI EINLLGCNMF SYSVNVEETY PGKLLLRV K DKVSELMPSI SQDSIIVSAN QYEVRINSEG RRELLDHSGE WINKEESIIK DISSKEYISF NPKENKIIVK SKNLPELST LLQEIRNNSN SSDIELEEKV MLAECEINVI SNIETQVVEE RIEEAKSLTS DSINYIKNEF KLIESISDAL YDLKQQNELE ESHFISFED ISKTDEGFSI RFIDKETGES IFVETEKAIF SEYANHITEE ISKLKDTIFD TVNGKLVKKV TLDATHEVNT L NAAFFIQS LIGYNSSKES LSNLSVAMKV QVYAQLFSTG LNTITDAAKV VELVSTALDE TIDLLPTLSE GLPVIATIID GV SLGASIK ELSETSDPLL RQEIEAKIGI MAVNLTAATT AIITSSLGIA SGFSILLVPL AGISAGIPSL VNNELILRAE AKN VVDYFG HISLAESEGA FTLLDDKIMM PQDDLVISEI DFNNNSITLG KCEIWRMEGG SGHTVTDDID HFFSAPSTTY REPY LSIYD VLDVKKEELD LSKDLMVLPN APDRIFGWER GWTPGLRSLE NDGTKLLDRI RDHYEGQFYW RFFAFIADSV ITKLK PRYE DTNIRISLDS NTRSFIVPVI TTEYIREKLS YSFYGSGGTY ALSLSQYNMN INIELNENDT WVIDVDNVVR DVTIES DKI KKGDLIENIL SKLSIEDNKI ILDNHEINFS GTLNGGNGFV SLTFSILEGI NAVIEVDLLS KSYKVLISGE LKTLMAN SN SVQQKIDYIG LNSELQKNIP YSFMDDEGKE NGFINCFTKE GLFVSELSDV VLIIKVYMDN SKPPFGYYSN DLKDVKVI T KDDVIILTGY YLKDDIKISL SFTIQDKNTI KLNGVYLDEN GVAEILKFMN KKGSTNTSDS LMSFLESMNI KSIFIKSLK SNAKLILDTN FIISGTTSIG QFEFICDKDN NIQPYFIKFN TLETKYTLYV GNRQNMIVEP NYNLDDSGDI SSTVINFSQK YLYGIDSCV NKVIISPNIY TDEINITPVH EANNTYPEVI VLDTNYISEK INININDLSI RYVWSNDGSD FILMSTDEEN K VSQVKIRF TNVFKGNTIS DKISFNFSDK QDISINKIIS TFTPSYYVEG LLNYDLGLIS LYNEKFYINN LGMMVSGLVY IN DSLYYFK PPIKNLITGF TTIGDDKYYF NPDNGGAASV GETIIDGKNY YFSQNGVLQT GVFSTEDGFK YFAPADTLDE NLE GEAIDF TGKLIIDENV YYFGDNYRAA IEWQTLDDEV YYFSTDTGRA FKGLNQIGDD KFYFNSDGIM QKGFVNINDK TFYF DDSGV MKSGYTEIDG KYFYFAENGE MQIGVFNTAD GFKYFAHHDE DLGNEEGEAL SYSGILNFNN KIYYFDDSFT AVVGW KDLE DGSKYYFDEN TAEASIGISI INDGKYYFND SGIMQIGFVT INNEVFYFSD SGIVESGMQN IDDNYFYISE NGLVQI GVF DTSDGYKYFA PANTVNDNIY GQAVEYSGLV RVNEDVYSFG ESYTIETGWI YDSENESDKY YFDPETKKAY KGINVID DI KYYFDENGIM RTGLITFEDN HYYFNEDGEM QYGYLNIEDK MFYFSEDGIM QIGVFNTPDG FKYFAHQNTL DENFEGES I NYTGWLDLDE KRYYFTDEYI AATGSVIIDG EEYYFDPDTA QLVISEHHHH HHHH

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Macromolecule #2: Isoform Beta of Tissue factor pathway inhibitor

MacromoleculeName: Isoform Beta of Tissue factor pathway inhibitor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.681633 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MIYTMKKVHA LWASVCLLLN LAPAPLNADS EEDEEHTIIT DTELPPLKLM HSFCAFKADD GPCKAIMKRF FFNIFTRQCE EFIYGGCEG NQNRFESLEE CKKMCTRDNA NRIIKTTLQQ EKPDFCFLEE DPGICRGYIT RYFYNNQTKQ CERFKYGGCL G NMNNFETL ...String:
MIYTMKKVHA LWASVCLLLN LAPAPLNADS EEDEEHTIIT DTELPPLKLM HSFCAFKADD GPCKAIMKRF FFNIFTRQCE EFIYGGCEG NQNRFESLEE CKKMCTRDNA NRIIKTTLQQ EKPDFCFLEE DPGICRGYIT RYFYNNQTKQ CERFKYGGCL G NMNNFETL EECKNICEDG PNGFQVDNYG TQLNAVNNSL TPQSTKVPSL FVTKEGTNDG WKNAAHIYQV FLNAFCIHAS MF FLGLDSI SCLC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 227825
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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