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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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Related in: MedlinePlus

A cartoon representation of the LmDHCH homodimer. Subunit A is yellow, B is green. The elements of secondary structure of subunit B are labeled in addition to the N- and C-termini. A small section of a loop (residues 248–250, highlighted with black asterisks) is absent in subunit B due to disorder.
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fig0015: A cartoon representation of the LmDHCH homodimer. Subunit A is yellow, B is green. The elements of secondary structure of subunit B are labeled in addition to the N- and C-termini. A small section of a loop (residues 248–250, highlighted with black asterisks) is absent in subunit B due to disorder.

Mentions: The crystal structure of LmDHCH has been determined at 2.7 Å resolution. The asymmetric unit is a homodimer and subunits are labeled A and B (Fig. 2). There was no evidence of a monomer in solution and the presence of a stable dimer is consistent with gel filtration data and in common with all other DHCH orthologues [19,42]. The first and last few residues (1–2 and 1–3, 297–298 in chains A and B, respectively) are disordered and an additional three residues are disordered in chain B (248–250). Superposition of subunit A onto subunit B gives an RMSD of 1.7 Å over 286 main chain Cα atoms. This high value reflects differences in domain positions, which will be discussed, and in a loop adjacent to the active site (residues 240–255; RMSD 4.1 Å over 13 Cα). This loop is disordered and absent in other DHCH structures and in LmDHCH, although modelled satisfactorily, elevated thermal parameters are noted.


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)

A cartoon representation of the LmDHCH homodimer. Subunit A is yellow, B is green. The elements of secondary structure of subunit B are labeled in addition to the N- and C-termini. A small section of a loop (residues 248–250, highlighted with black asterisks) is absent in subunit B due to disorder.
© Copyright Policy
Related In: Results  -  Collection

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

fig0015: A cartoon representation of the LmDHCH homodimer. Subunit A is yellow, B is green. The elements of secondary structure of subunit B are labeled in addition to the N- and C-termini. A small section of a loop (residues 248–250, highlighted with black asterisks) is absent in subunit B due to disorder.
Mentions: The crystal structure of LmDHCH has been determined at 2.7 Å resolution. The asymmetric unit is a homodimer and subunits are labeled A and B (Fig. 2). There was no evidence of a monomer in solution and the presence of a stable dimer is consistent with gel filtration data and in common with all other DHCH orthologues [19,42]. The first and last few residues (1–2 and 1–3, 297–298 in chains A and B, respectively) are disordered and an additional three residues are disordered in chain B (248–250). Superposition of subunit A onto subunit B gives an RMSD of 1.7 Å over 286 main chain Cα atoms. This high value reflects differences in domain positions, which will be discussed, and in a loop adjacent to the active site (residues 240–255; RMSD 4.1 Å over 13 Cα). This loop is disordered and absent in other DHCH structures and in LmDHCH, although modelled satisfactorily, elevated thermal parameters are noted.

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