8R7U
Crystal Structure of Cyclophilin TgCyp23 from Toxoplasma gondii in complex with dihydro Cyclosporin A
Summary for 8R7U
| Entry DOI | 10.2210/pdb8r7u/pdb |
| Related | 8R7S 8R7T |
| Related PRD ID | PRD_002553 |
| Descriptor | Peptidyl-prolyl cis-trans isomerase, Dihydrocyclosporin A (3 entities in total) |
| Functional Keywords | cyclophilin complex, peptidylprolyl isomerase activity, isomerase |
| Biological source | Toxoplasma gondii More |
| Total number of polymer chains | 4 |
| Total formula weight | 48831.95 |
| Authors | |
| Primary citation | Favretto, F.,Jimenez-Faraco, E.,Catucci, G.,Di Matteo, A.,Travaglini-Allocatelli, C.,Sadeghi, S.J.,Dominici, P.,Hermoso, J.A.,Astegno, A. Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies. Protein Sci., 33:e5157-e5157, 2024 Cited by PubMed Abstract: Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response. PubMed: 39312281DOI: 10.1002/pro.5157 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.2 Å) |
Structure validation
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