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The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.

Eadsforth TC, Cameron S, Hunter WN - Mol. Biochem. Parasitol. (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

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Stereo view Cα trace showing the superposition of a subunit of LmDHCH (green) with an equivalent from HsDHCH (marine) ternary complex with NADP+ (yellow) and LY354899 (black) (PDB code 1DIB). In both cases a loop that remains disordered is marked with two asterisks.
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fig0030: Stereo view Cα trace showing the superposition of a subunit of LmDHCH (green) with an equivalent from HsDHCH (marine) ternary complex with NADP+ (yellow) and LY354899 (black) (PDB code 1DIB). In both cases a loop that remains disordered is marked with two asterisks.

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.


The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target.

Eadsforth TC, Cameron S, Hunter WN - Mol. Biochem. Parasitol. (2011)

Stereo view Cα trace showing the superposition of a subunit of LmDHCH (green) with an equivalent from HsDHCH (marine) ternary complex with NADP+ (yellow) and LY354899 (black) (PDB code 1DIB). In both cases a loop that remains disordered is marked with two asterisks.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368264&req=5

fig0030: Stereo view Cα trace showing the superposition of a subunit of LmDHCH (green) with an equivalent from HsDHCH (marine) ternary complex with NADP+ (yellow) and LY354899 (black) (PDB code 1DIB). In both cases a loop that remains disordered is marked with two asterisks.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

Show MeSH
Related in: MedlinePlus