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PDBsum entry 1pd8
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Oxidoreductase
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PDB id
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1pd8
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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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Analysis of three crystal structure determinations of a 5-Methyl-6-N-Methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase.
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Authors
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V.Cody,
J.R.Luft,
W.Pangborn,
A.Gangjee.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2003,
59,
1603-1609.
[DOI no: ]
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PubMed id
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Abstract
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Structural data are reported for the first example of the potent antifolate
inhibitor
2,4-diamino-5-methyl-6-[(3',4',5'-trimethoxy-N-methylanilino)methyl]pyrido[2,3-d]pyrimidine
(1) in complex with human dihydrofolate reductase (hDHFR) and NADPH. Small
differences in crystallization conditions resulted in the growth of two
different forms of a binary complex. The structure determination of an
additional crystal of a ternary complex of hDHFR with NADPH and (1) grown under
similar conditions is also reported. Diffraction data were collected to 2.1 A
resolution for an R3 lattice from a hDHFR ternary complex with NADPH and (1) and
to 2.2 A resolution from a binary complex. Data were also collected to 2.1 A
resolution from a binary complex with hDHFR and (1) in the first example of a
tetragonal P4(3)2(1)2 lattice. Comparison of the intermolecular contacts among
these structures reveals differences in the backbone conformation (1.9-3.2 A)
for flexible loop regions (residues 40-46, 77-83 and 103-107) that reflect
differences in the packing environment between the rhombohedral and tetragonal
space groups. Analysis of the packing environments shows that the tetragonal
lattice is more tightly packed, as reflected in its smaller V(M) value and lower
solvent content. The conformation of the inhibitor (1) is similar in all
structures and is also similar to that observed for TMQ, the parent quinazoline
compound. The activity profile for this series of 5-deaza N-substituted
non-classical trimethoxybenzyl antifolates shows that the N10-CH(3) substituted
(1) has the greatest potency and selectivity for Toxoplasma gondii DHFR (tgDHFR)
compared with its N-H or N-CHO analogs. Models of the tgDHFR active site
indicate preferential contacts with (1) that are not present in either the human
or Pneumocystis carinii DHFR structures. Differences in the acidic residue
(Glu30 versus Asp for tgDHFR) affect the precise positioning of the
diaminopyridopyrimidine ring, while changes in other residues, particularly at
positions 60 and 64 (Leu versus Met and Asn versus Phe), involve interactions
with the trimethoxybenzyl substituents.
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Figure 1.
Figure 1 Schematic representation of trimethoprim (TMP),
trimetrexate (TMQ) and its pyridopyrimidine N10-substituted
analogs.
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Figure 4.
Figure 4 Comparison of active-site binding region of hDHFR with
NADPH and antifolate (1) for the R3 lattice (cyan) and for the
P4[3]2[1]2 lattice (yellow). Also shown is F31A hDHFR-TMQ
(violet). Models were 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
(2003,
59,
1603-1609)
copyright 2003.
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