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PDBsum entry 1s3y
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Oxidoreductase
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PDB id
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1s3y
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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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Structure determination of tetrahydroquinazoline antifolates in complex with human and pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry.
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Authors
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V.Cody,
J.R.Luft,
W.Pangborn,
A.Gangjee,
S.F.Queener.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2004,
60,
646-655.
[DOI no: ]
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PubMed id
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Abstract
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Structural data are reported for the first examples of the tetrahydroquinazoline
antifolate
(6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline (1) and
its trimethoxy analogue
(6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydroquinazoline
(2) as inhibitor complexes with dihydrofolate reductase (DHFR) from human
(hDHFR) and Pneumocystis carinii (pcDHFR) sources. The indoline analogue (1) was
crystallized as ternary complexes with NADPH and hDHFR (1.9 A resolution) and
pcDHFR (2.3 A resolution), while the trimethoxy quinazoline analogue (2) was
crystallized as a binary complex with hDHFR in two polymorphic rhombohedral R3
lattices: R3(1) to 1.8 A resolution and R3(2) to 2.0 A resolution. Structural
analysis of these potent and selective DHFR-inhibitor complexes revealed
preferential binding of the 6S-equatorial isomer in each structure. This
configuration is similar to that of the natural tetrahydrofolate substrate; that
is, 6S. These data also show that in both the hDHFR and pcDHFR ternary complexes
with (1) the indoline ring is partially disordered, with two static
conformations that differ between structures. These conformers also differ from
that observed for the trimethoxybenzyl ring of tetrahydroquinazoline (2). There
is also a correlation between the disorder of the flexible loop 23 and the
disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1)
ternary complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR) sequence with
those of other DHFRs provides insight into the role of sequence and conformation
in inhibitor-binding preferences which may aid in the design of novel
antifolates with specific DHFR selectivity.
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Figure 2.
Figure 2 Orientation of the pteridine ring for folates (cyan)
and antifolates (red). The Connolly surface for hDHFR is shown
in green and the contact distances of the nicotinamide ring of
NADPH are shown to the folate-reduction site.
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Figure 8.
Figure 8 Comparison of the binding of inhibitor (1) to human
DHFR (violet) and pcDHFR (yellow). In each structure the
indoline ring of (1) is disordered. There are two orientations
observed in the human DHFR structure (violet) and two
orientations observed in the pcDHFR complex (green and cyan).
Diagram produced with SETOR (Evans, 1993[Evans, S. V. (1993). J.
Mol. Graph. 11, 134-138.]).
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2004,
60,
646-655)
copyright 2004.
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