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- PDB-8jhz: Cryo-EM structure of the TcsH-TMPRSS2 complex -

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Basic information

Entry
Database: PDB / ID: 8jhz
TitleCryo-EM structure of the TcsH-TMPRSS2 complex
Components
  • Hemorrhagic toxin
  • Transmembrane protease serine 2
KeywordsTOXIN/HYDROLASE / TcsH / TMPESS2 / TOXIN-HYDROLASE complex
Function / homology
Function and homology information


transmembrane protease serine 2 / host cell cytosol / glycosyltransferase activity / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / host cell endosome membrane / peptidase activity / toxin activity / viral translation ...transmembrane protease serine 2 / host cell cytosol / glycosyltransferase activity / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / host cell endosome membrane / peptidase activity / toxin activity / viral translation / Induction of Cell-Cell Fusion / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / lipid binding / host cell plasma membrane / proteolysis / extracellular exosome / extracellular region / nucleoplasm / metal ion binding / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain ...Scavenger receptor cysteine-rich domain / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical 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. / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Nucleotide-diphospho-sugar transferases / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Hemorrhagic toxin / Transmembrane protease serine 2
Similarity search - Component
Biological speciesPaeniclostridium sordellii (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 3.2 Å
AuthorsZhou, R. / Liang, T. / Zhan, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.
Authors: Ruoyu Zhou / Liuqing He / Jiahao Zhang / Xiaofeng Zhang / Yanyan Li / Xiechao Zhan / Liang Tao /
Abstract: Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane ...Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.
History
DepositionMay 25, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hemorrhagic toxin
B: Transmembrane protease serine 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)347,4543
Polymers347,3882
Non-polymers651
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Hemorrhagic toxin


Mass: 300675.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Paeniclostridium sordellii (bacteria) / Gene: tcsH / Production host: Bacillus subtilis (bacteria) / References: UniProt: M9ZTT7
#2: Protein Transmembrane protease serine 2 / Serine protease 10


Mass: 46712.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS2, PRSS10 / Production host: Homo sapiens (human)
References: UniProt: O15393, transmembrane protease serine 2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN

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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

ComponentName: The TcsH-TMPRSS2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Paeniclostridium sordellii (bacteria)1505
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Bacillus subtilis (bacteria)1432
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO

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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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
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: 87378 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00719712
ELECTRON MICROSCOPYf_angle_d0.63926693
ELECTRON MICROSCOPYf_dihedral_angle_d5.3162568
ELECTRON MICROSCOPYf_chiral_restr0.0482951
ELECTRON MICROSCOPYf_plane_restr0.0043435

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