Limits...
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.

Show MeSH

Related in: MedlinePlus

Structure-based sequence alignment of L. major and H. sapiens cytosolic DHCH enzymes. Helices and strands are red and blue, respectively. Residues that are strictly or highly conserved in H. sapiens, L. major, T. brucei, T. cruzi and L. donovani enzymes are highlighted in black and grey, respectively. Residues that directly bind ligands (as shown in the HsDHCH structures) are marked with a yellow star and are highly conserved across all species. Residues that are within 5 Å of the bound ligand in the HsDHCH structure are enclosed in green boxes.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3368264&req=5

fig0025: Structure-based sequence alignment of L. major and H. sapiens cytosolic DHCH enzymes. Helices and strands are red and blue, respectively. Residues that are strictly or highly conserved in H. sapiens, L. major, T. brucei, T. cruzi and L. donovani enzymes are highlighted in black and grey, respectively. Residues that directly bind ligands (as shown in the HsDHCH structures) are marked with a yellow star and are highly conserved across all species. Residues that are within 5 Å of the bound ligand in the HsDHCH structure are enclosed in green boxes.

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)

Structure-based sequence alignment of L. major and H. sapiens cytosolic DHCH enzymes. Helices and strands are red and blue, respectively. Residues that are strictly or highly conserved in H. sapiens, L. major, T. brucei, T. cruzi and L. donovani enzymes are highlighted in black and grey, respectively. Residues that directly bind ligands (as shown in the HsDHCH structures) are marked with a yellow star and are highly conserved across all species. Residues that are within 5 Å of the bound ligand in the HsDHCH structure are enclosed in green boxes.
© Copyright Policy
Related In: Results  -  Collection

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

fig0025: Structure-based sequence alignment of L. major and H. sapiens cytosolic DHCH enzymes. Helices and strands are red and blue, respectively. Residues that are strictly or highly conserved in H. sapiens, L. major, T. brucei, T. cruzi and L. donovani enzymes are highlighted in black and grey, respectively. Residues that directly bind ligands (as shown in the HsDHCH structures) are marked with a yellow star and are highly conserved across all species. Residues that are within 5 Å of the bound ligand in the HsDHCH structure are enclosed in green boxes.
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