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Two Crystal Structures Of Dihydrofolate Reductase-Thymidylate Synthase From Cryptosporidium Hominis Reveal Protein–Ligand Interactions Including A Structural Basis For Observed Antifolate Resistance, Amy C. Anderson
Dartmouth Scholarship
Cryptosporidium hominis is a protozoan parasite that causes acute gastro- intestinal 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 AÊ 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 …