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- PDB-7ml7: Structural basis for CSPG4 as a receptor for TcdB and a therapeut... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7ml7 | ||||||
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Title | Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection | ||||||
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![]() | TOXIN / CSPG4 / TcdB / Clostridioides difficile infection | ||||||
Function / homology | ![]() Chondroitin sulfate biosynthesis / Defective CHST3 causes SEDCJD / Defective CHST14 causes EDS, musculocontractural type / Defective CHSY1 causes TPBS / Dermatan sulfate biosynthesis / Defective B3GALT6 causes EDSP2 and SEMDJL1 / CS/DS degradation / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD / substrate-dependent cell migration ...Chondroitin sulfate biosynthesis / Defective CHST3 causes SEDCJD / Defective CHST14 causes EDS, musculocontractural type / Defective CHSY1 causes TPBS / Dermatan sulfate biosynthesis / Defective B3GALT6 causes EDSP2 and SEMDJL1 / CS/DS degradation / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD / substrate-dependent cell migration / A tetrasaccharide linker sequence is required for GAG synthesis / glial cell migration / tissue remodeling / ruffle assembly / glucosyltransferase activity / Differentiation of keratinocytes in interfollicular epidermis in mammalian skin / host cell cytosol / Transferases; Glycosyltransferases; Hexosyltransferases / lamellipodium membrane / platelet-derived growth factor receptor signaling pathway / coreceptor activity / cysteine-type peptidase activity / ruffle / lysosomal lumen / host cell endosome membrane / Golgi lumen / positive regulation of peptidyl-tyrosine phosphorylation / toxin activity / angiogenesis / collagen-containing extracellular matrix / positive regulation of MAPK cascade / Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases / intracellular signal transduction / apical plasma membrane / focal adhesion / lipid binding / protein kinase binding / host cell plasma membrane / cell surface / proteolysis / extracellular exosome / extracellular region / nucleoplasm / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å | ||||||
![]() | Chen, P. / Jin, R. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection. Authors: Peng Chen / Ji Zeng / Zheng Liu / Hatim Thaker / Siyu Wang / Songhai Tian / Jie Zhang / Liang Tao / Craig B Gutierrez / Li Xing / Ralf Gerhard / Lan Huang / Min Dong / Rongsheng Jin / ![]() ![]() ![]() Abstract: C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and ...C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for TcdB, but its pathophysiological relevance and the molecular details that govern recognition remain unknown. Here, we determine the cryo-EM structure of a TcdB-CSPG4 complex, revealing a unique binding site spatially composed of multiple discontinuous regions across TcdB. Mutations that selectively disrupt CSPG4 binding reduce TcdB toxicity in mice, while CSPG4-knockout mice show reduced damage to colonic tissues during C. difficile infections. We further show that bezlotoxumab, the only FDA approved anti-TcdB antibody, blocks CSPG4 binding via an allosteric mechanism, but it displays low neutralizing potency on many TcdB variants from epidemic hypervirulent strains due to sequence variations in its epitopes. In contrast, a CSPG4-mimicking decoy neutralizes major TcdB variants, suggesting a strategy to develop broad-spectrum therapeutics against TcdB. | ||||||
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 281.6 KB | Display | ![]() |
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PDB format | ![]() | 211.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 23909MC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 228752.531 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P18177, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases |
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#2: Protein | Mass: 82298.305 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: Mammalian expression vector BsrGI-MCS-pcDNA3.1 (others) References: UniProt: Q6UVK1 |
#3: Chemical | ChemComp-ZN / |
Has ligand of interest | N |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177995 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 63.27 Å2 | ||||||||||||||||||||||||
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