8r7t

Crystal Structure of Cyclophilin TgCyp23 from Toxoplasma gondii in complex with Alisporivir (nonimmunosuppressive analogue of Cyclosporin)

spinqualitylabelsall models 8r7t, resolution 1.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8r7t is a 4 chain structure with sequence from Toxoplasma gondii and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.2Å Ligands: 33X, 66E, ABA, BMT, DAL, MLE, MVA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A7J6KAD1_TOXGO PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.[RuleBase:RU363019] Publication Abstract from PubMed 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. Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.,Favretto F, Jimenez-Faraco E, Catucci G, Di Matteo A, Travaglini-Allocatelli C, Sadeghi SJ, Dominici P, Hermoso JA, Astegno A Protein Sci. 2024 Oct;33(10):e5157. doi: 10.1002/pro.5157. PMID:39312281 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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