8YVO
Crystal structure of the C. difficile toxin A CROPs domain fragment 2639-2707 bound to C4.2 nanobody
Summary for 8YVO
| Entry DOI | 10.2210/pdb8yvo/pdb |
| Descriptor | C4.2 nanobody, Toxin A, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | crops domain fragment, toxin a, complex with nanobody, clostridioides difficile, toxin, toxin-immune system complex, toxin/immune system |
| Biological source | Camelus dromedarius More |
| Total number of polymer chains | 4 |
| Total formula weight | 52969.65 |
| Authors | Sluchanko, N.N.,Varfolomeeva, L.A.,Shcheblyakov, D.V.,Belyi, Y.F.,Logunov, D.Y.,Gintsburg, A.L.,Popov, V.O.,Boyko, K.M. (deposition date: 2024-03-28, release date: 2024-12-18) |
| Primary citation | Sluchanko, N.N.,Sokolova, I.V.,Favorskaya, I.A.,Esmagambetov, I.B.,Tukhvatulin, A.I.,Alekseeva, I.A.,Ungur, A.S.,Varfolomeeva, L.A.,Boyko, K.M.,Logunov, D.Y.,Gintsburg, A.L.,Popov, V.O.,Shcheblyakov, D.V.,Belyi, Y.F. Structural insight into recognition of Clostridioides difficile toxin A by novel neutralizing nanobodies targeting QTIN-like motifs within its receptor-binding domain. Int.J.Biol.Macromol., 283:137910-137910, 2024 Cited by PubMed Abstract: Clostridioides difficile causes a large proportion of nosocomial colon infections by producing toxins TcdA and TcdB as key virulence factors. TcdA and TcdB have analogous domain structures with a receptor-binding domain containing C-terminal combined repetitive oligopeptides (CROPs), an attractive target for the development of therapeutic antibodies. Here, we identify and characterize two potent neutralizing single-domain camelid anti-CROPsA antibodies, C4.2 and H5.2, with distinct mechanisms of action. Peptide mapping, high-resolution crystal structures and site-directed mutagenesis revealed that C4.2 and H5.2 nanobodies target the same C-terminal epitope centered on a QTIN motif, yet utilize different paratopes. Only for C4.2 is the complex geometry compatible with multisite binding using QTIN-like repeats throughout the CROPsA domain, as supported by Western blotting, ELISA, and SEC-MALS analysis. H5.2 binding is stronger and more selective for the C-terminal epitope than C4.2, although both nanobodies are sufficient to neutralize TcdA individually. The described epitope does not overlap with previously described epitopes of anti-CROPs antibodies and provides new modalities for disease treatment and diagnostics. PubMed: 39577542DOI: 10.1016/j.ijbiomac.2024.137910 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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