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PDBsum entry 2bf7
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Oxidoreductase
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PDB id
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2bf7
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References listed in PDB file
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Key reference
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Title
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Structures of leishmania major pteridine reductase complexes reveal the active site features important for ligand binding and to guide inhibitor design.
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Authors
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A.W.Schüttelkopf,
L.W.Hardy,
S.M.Beverley,
W.N.Hunter.
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Ref.
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J Mol Biol, 2005,
352,
105-116.
[DOI no: ]
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PubMed id
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Abstract
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Pteridine reductase (PTR1) is an NADPH-dependent short-chain reductase found in
parasitic trypanosomatid protozoans. The enzyme participates in the salvage of
pterins and represents a target for the development of improved therapies for
infections caused by these parasites. A series of crystallographic analyses of
Leishmania major PTR1 are reported. Structures of the enzyme in a binary complex
with the cofactor NADPH, and ternary complexes with cofactor and biopterin,
5,6-dihydrobiopterin, and 5,6,7,8-tetrahydrobiopterin reveal that PTR1 does not
undergo any major conformational changes to accomplish binding and processing of
substrates, and confirm that these molecules bind in a single orientation at the
catalytic center suitable for two distinct reductions. Ternary complexes with
cofactor and CB3717 and trimethoprim (TOP), potent inhibitors of thymidylate
synthase and dihydrofolate reductase, respectively, have been characterized. The
structure with CB3717 reveals that the quinazoline moiety binds in similar
fashion to the pterin substrates/products and dominates interactions with the
enzyme. In the complex with TOP, steric restrictions enforced on the
trimethoxyphenyl substituent prevent the 2,4-diaminopyrimidine moiety from
adopting the pterin mode of binding observed in dihydrofolate reductase, and
explain the inhibition properties of a range of pyrimidine derivates. The
molecular detail provided by these complex structures identifies the important
interactions necessary to assist the structure-based development of novel enzyme
inhibitors of potential therapeutic value.
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Figure 2.
Figure 2. The chemical structures of three PTR1 inhibitors:
methotrexate, CB3717 and trimethoprim. The molecules are
depicted in a similar orientation in all Figures. The
methotrexate molecule is depicted with the pterin-ring flipped
about the N2-N5 axis relative to other pterins as actually
observed in the PTR1 active site.
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Figure 6.
Figure 6. CB3717 binding to LmPTR1. (a) Stereoview showing
the omit difference density map (contoured at 2.4s) as described
for Figure 3. The same color scheme as Figure 3 is used with the
addition that the glutamate tail of the inhibitor is red and
broken lines represent potential hydrogen bonds. Phe113 is
depicted as a semitransparent object. (b) A representation of
the active site with the ligand in similar fashion to Figure 4.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
352,
105-116)
copyright 2005.
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