8B58

Crystal Structure of Cyclophilin TgCyp23 from Toxoplasma gondii in complex with Cyclosporin A

Summary for 8B58

• Entry DOI: 10.2210/pdb8b58/pdb
• Related PRD ID: PRD_000142
• Descriptor: Peptidyl-prolyl cis-trans isomerase, Cyclosporin A (3 entities in total)
• Functional Keywords: cyclophilin, isomerase-immunosuppressant complex, isomerase
• Biological source: Toxoplasma gondii; More
• Total number of polymer chains: 4
• Total formula weight: 48437.53

Authors

Jimenez-Faraco, E.,Hermoso, J.A. (deposition date: 2022-09-22, release date: 2023-02-01, Last modification date: 2023-02-22)

Primary citation

Favretto, F.,Jimenez-Faraco, E.,Conter, C.,Dominici, P.,Hermoso, J.A.,Astegno, A.
Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii .
Acs Infect Dis., 9:365-377, 2023

PubMed Abstract: Cyclosporin (CsA) has antiparasite activity against the human pathogen . A possible mechanism of action involves CsA binding to cyclophilins, although much remains to be understood. Herein, we characterize the functional and structural properties of a conserved (TgCyp23) and a more divergent (TgCyp18.4) cyclophilin isoform from . While TgCyp23 is a highly active cis-trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at the atomic resolution showing the molecular details of CsA recognition by the protein. Computational and structural studies revealed relevant differences at the CsA-binding site between TgCyp18.4 and TgCyp23, suggesting that the two cyclophilins might have distinct functions in the parasite. These studies highlight the extensive diversification of TgCyps and pave the way for antiparasite interventions based on selective targeting of cyclophilins.

PubMed: 36653744
DOI: 10.1021/acsinfecdis.2c00566

Experimental method

X-RAY DIFFRACTION (1.1 Å)