7ml7

Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection

spinqualitylabelsall models 7ml7, resolution 3.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ml7 is a 2 chain structure with sequence from Clostridioides difficile and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.17Å Ligands: ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TCDB_CLODI Precursor of a cytotoxin that targets and disrupts the colonic epithelium, inducing the host inflammatory and innate immune responses and resulting in diarrhea and pseudomembranous colitis (PubMed:20844489, PubMed:24919149). TcdB constitutes the main toxin that mediates the pathology of C.difficile infection, an opportunistic pathogen that colonizes the colon when the normal gut microbiome is disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdA, TcdB is more virulent and more important for inducing the host inflammatory and innate immune responses (PubMed:19252482, PubMed:24919149). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdB) into the host cytosol (PubMed:10768933, PubMed:11152463, PubMed:12941936, PubMed:17334356, PubMed:20498856). Targets colonic epithelia by binding to the frizzled receptors FZD1, FZD2 and FZD7, and enters host cells via clathrin-mediated endocytosis (PubMed:27680706). Frizzled receptors constitute the major host receptors in the colonic epithelium, but other receptors, such as CSPG4 or NECTIN3/PVRL3, have been identified (PubMed:25547119, PubMed:26038560, PubMed:27680706). Binding to carbohydrates and sulfated glycosaminoglycans on host cell surface also contribute to entry into cells (By similarity). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (PubMed:11152463, PubMed:12941936, PubMed:24567384). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcdB), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:27571750).[UniProtKB:P16154] Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149, PubMed:7777059, PubMed:8144660). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, RhoG and Cdc42) in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor (PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149, PubMed:7777059). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:24919149, PubMed:7777059). Publication Abstract from PubMed 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. Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection.,Chen P, Zeng J, Liu Z, Thaker H, Wang S, Tian S, Zhang J, Tao L, Gutierrez CB, Xing L, Gerhard R, Huang L, Dong M, Jin R Nat Commun. 2021 Jun 18;12(1):3748. doi: 10.1038/s41467-021-23878-3. PMID:34145250 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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