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PDBsum entry 1w0c
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Oxidoreductase
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PDB id
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1w0c
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Inhibition of leishmania major pteridine reductase by 2,4,6-Triaminoquinazoline: structure of the NADPH ternary complex.
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Authors
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K.Mcluskey,
F.Gibellini,
P.Carvalho,
M.A.Avery,
W.N.Hunter.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2004,
60,
1780-1785.
[DOI no: ]
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PubMed id
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Abstract
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The structure of Leishmania major pteridine reductase (PTR1) in complex with
NADPH and the inhibitor 2,4,6-triaminoquinazoline (TAQ) has been solved in a new
crystal form by molecular replacement and refined to 2.6 A resolution. The
inhibitor mimics a fragment, the pterin head group, of the archetypal antifolate
drug methotrexate (MTX) and exploits similar chemical features to bind in the
PTR1 active site. Despite being a much smaller molecule, TAQ displays a similar
inhibition constant to that of MTX. PTR1 is a target for the development of
improved therapies for infections caused by trypanosomatid parasites and this
analysis provides information to assist the structure-based development of novel
enzyme inhibitors.
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Figure 3.
Figure 3 The active-site cleft of PTR1. The surface of subunit A
is shown in grey, the surface of subunit B in green and Arg287'
from subunit D in blue. The cofactor and inhibitor are
represented in stick mode and coloured according to atom type:
N, blue; O, red; P, pink; C, yellow for NADPH and black for TAQ.
Selected residues that line the active-site cleft are labelled.
Figs. 3, 4 and 5 were prepared with PyMOL (DeLano, 2002[100]
[DeLano, W. L. (2002). The PyMOL Molecular Graphics System.
DeLano Scientific, San Carlos, CA, USA.]-[101][bluearr.gif] ).
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Figure 4.
Figure 4 Hydrogen-bonding interactions at the site of
inhibition. A similar colour scheme to Figs. 2 and 3 is adopted;
in addition, water molecules are depicted as marine-coloured
spheres. Marine dashed lines represent possible hydrogen-bonding
associations and a red dashed line represents the C-H
[107][\cdots] O interaction between C5 (*) and the carbonyl of
Gly225.
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2004,
60,
1780-1785)
copyright 2004.
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