Cyclosporin (CsA) has antiparasite activity against the
human pathogen Toxoplasma gondii. A
possible mechanism of action
involves CsA binding to T. gondii 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 T. gondii. 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.
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