The crystal structure of protease Sapp1p from Candida parapsilosis in complex with the HIV protease inhibitor ritonavir

Abstract

Secreted aspartic proteases (Saps) are extracellular proteolytic enzymes that enhance the virulence of Candida pathogens. These enzymes therefore represent possible targets for therapeutic drug design. Saps are inhibited by nanomolar concentrations of the classical inhibitor of aspartic proteases pepstatin A and also by the inhibitors of the HIV protease, but with the K_i of micromolar values or higher. To contribute to the discussion regarding whether HIV protease inhibitors can act against opportunistic mycoses by the inhibition of Saps, we determined the structure of Sapp1p from Candida parapsilosis in complex with ritonavir (RTV), a clinically used inhibitor of the HIV protease. The crystal structure refined at resolution 2.4 Å proved binding of RTV into the active site of Sapp1p and provided the structural information necessary to evaluate the stability and specificity of the protein-inhibitor interaction.

Keywords::

• Secreted aspartic protease
• virulence factor
• X-ray structure
• candidiasis

Acknowledgements

This work was supported by research projects AV0Z40550506, and AV0Z50520514 awarded by the Academy of Sciences of the Czech Republic. Additional support was awarded also by Ministry of Education of the Czech Republic (grant LC 531), and by the Czech Science Foundation (grants 310/09/1945 and 203/09/0820). Diffraction data were collected on beamline MX14.2 at BESSY, Berlin, Germany. The authors wish to thank Devon Maloy for critical proofreading of the manuscript.

Declaration of interest

The authors declare no conflicts of interest.