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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

An overlay of the LmDHCH subunits based on superposition of N-terminal domains. The N-terminal domains (chain A – blue, chain B – cyan) agree closely however a pivot (shown in green for chain A and forest for chain B) causes the C-terminal domains (chain A – red, chain B – magenta) to differ by approximately 14°. Such a shift appears accentuated particularly around the loop leading to β10.
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fig0020: An overlay of the LmDHCH subunits based on superposition of N-terminal domains. The N-terminal domains (chain A – blue, chain B – cyan) agree closely however a pivot (shown in green for chain A and forest for chain B) causes the C-terminal domains (chain A – red, chain B – magenta) to differ by approximately 14°. Such a shift appears accentuated particularly around the loop leading to β10.

Mentions: The LmDHCH subunit consists of 298 residues displaying a high level of secondary structure; 11 α-helices and 11 β-strands (Fig. 2). The polypeptide folds into N- and C-terminal domains comprising residues 5–147 and 148–298, respectively. A cleft is formed between the two domains and at one end an NADP+ binding site, typical of a Rossmann fold (βαβαβ), is formed. The substrate-binding site is at the other end of the cleft. Analysis of the domains of LmDHCH from the crystallographically independent chains shows a significant pivot around a hinge (residues 150–152 and 274–280) with a rotation of almost 14° evident (Fig. 3). The hinge involves α6 and the loop leading into α11. A similar observation has been made in HsDHCH structures [19,20]. The subunits appear in distinct states, with the active site slightly more compressed in one than the other and this may represent a feature of DHCH activity.


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)

An overlay of the LmDHCH subunits based on superposition of N-terminal domains. The N-terminal domains (chain A – blue, chain B – cyan) agree closely however a pivot (shown in green for chain A and forest for chain B) causes the C-terminal domains (chain A – red, chain B – magenta) to differ by approximately 14°. Such a shift appears accentuated particularly around the loop leading to β10.
© Copyright Policy
Related In: Results  -  Collection

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

fig0020: An overlay of the LmDHCH subunits based on superposition of N-terminal domains. The N-terminal domains (chain A – blue, chain B – cyan) agree closely however a pivot (shown in green for chain A and forest for chain B) causes the C-terminal domains (chain A – red, chain B – magenta) to differ by approximately 14°. Such a shift appears accentuated particularly around the loop leading to β10.
Mentions: The LmDHCH subunit consists of 298 residues displaying a high level of secondary structure; 11 α-helices and 11 β-strands (Fig. 2). The polypeptide folds into N- and C-terminal domains comprising residues 5–147 and 148–298, respectively. A cleft is formed between the two domains and at one end an NADP+ binding site, typical of a Rossmann fold (βαβαβ), is formed. The substrate-binding site is at the other end of the cleft. Analysis of the domains of LmDHCH from the crystallographically independent chains shows a significant pivot around a hinge (residues 150–152 and 274–280) with a rotation of almost 14° evident (Fig. 3). The hinge involves α6 and the loop leading into α11. A similar observation has been made in HsDHCH structures [19,20]. The subunits appear in distinct states, with the active site slightly more compressed in one than the other and this may represent a feature of DHCH activity.

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