Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance.
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 A 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.
Anderson
Amy C
AC
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA. aca@dartmouth.edu
D000818:Animals; D001665:Binding Sites; D003458:Cryptosporidium / Q000201:enzymology*; D003460:Crystallization; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017356:Synchrotrons; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D013940:Thymidylate Synthase / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D014961:X-Ray Diffraction
D005493:Folic Acid Antagonists; D008024:Ligands; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase