The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.
Bottom Line: Here, we present the 2.7 Å resolution crystal structure of the bifunctional apo-DHCH from L. major, which is a potential drug target.Sequence alignments show that the cytosolic enzymes found in trypanosomatids share a high level of identity of approximately 60%.Additionally, residues that interact and participate in catalysis in the human homologue are conserved amongst trypanosomatid sequences and this may complicate attempts to derive potent, parasite specific DHCH inhibitors.
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.Show MeSH
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Mentions: The human and L. major enzymes share 44% sequence identity (Fig. 4) and the structures are similar. Superposition of LmDHCH subunits onto binary- or tertiary complexes of HsDHCH subunits in the same open or closed forms reveals RMSD values of approximately 1.0 Å over 270 Cα positions (Fig. 5). Superposition of the HsDHCH NADP+ binary and an NADP+-inhibitor tertiary complexes gives an RMSD of 0.1 Å over 285 Cα atoms, suggesting no gross structural change occurs following inhibitor binding.
Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.