Structural characteristics of antifolate dihydrofolate reductase enzyme interactions

Vivian Cody*, Carl H. Schwalbe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The ubiquitous enzyme dihydrofolate reductase (DHFR) is responsible for the reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate in an NADPH-dependent manner. It is also a key pharmacological target for the treatment of cancer, as well as bacterial and opportunistic pathogenic infections. Interest in the design of potent and selective antifolate inhibitors has made DHFR one of the most studied enzymes, in particular its structural and biochemical properties. This review surveys more than 129 DHFR solution and crystal structures currently (02/07) reported in the Protein Data Bank representing 15 species of enzyme. Comparison of these DHFR sequences shows that while there is a high sequence homology among vertebrate species (75-95%), there is only about 30% homology between vertebrate and bacterial species. Despite the highly conserved nature of the ligand and cofactor binding sites, DHFR can bind a wide range of compounds that can have a high degree of flexibility. The enzyme itself can also undergo ligand-induced conformational changes that reflect its catalytic mechanism of action. Mechanistic questions can now be addressed with the structural data available for atomic resolution enzyme complexes as well as from neutron diffraction data that have recently become available. These data provide new insight into the design of novel inhibitors that can target specific species with high selectivity of binding.

Original languageEnglish
Pages (from-to)301-333
Number of pages33
JournalCrystallography Reviews
Issue number4
Publication statusPublished - 1 Oct 2006


  • Active site topology
  • Conformational flexibility
  • Dihydrofolate reductase
  • Protein-protein interactions
  • Ring stacking


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