protein structure communications
Cryptosporidium hominis is a protozoan parasite that causes acute gastrointestinal illness. There are no effective therapies for cryptosporidiosis, highlighting the need for new drug-lead discovery. An analysis of the protein-ligand interactions in two crystal structures of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from C. hominis, determined at 2.8 and 2.87 Å resolution, reveals that the interactions of residues Ile29, Thr58 and Cys113 in the active site of C. hominis DHFR provide a possible structural basis for the observed antifolate resistance. A comparison with the structure of human DHFR reveals active-site differences that may be exploited for the design of species-selective inhibitors.
Keywords: dihydrofolate reductase-thymidylate synthase; structure-based drug design; cryptosporidiosis; antifolate resistance.
Supporting information
PDB references: ChDHFR-TS bound to NADPH/DHF/dUMP/CB3717, 1qzf, r1qzfsf; ChDHFR-TS bound to NADPH/1843U89/dUMP, 1sej, r1sejsf