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PDBsum entry 1cd2
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Oxidoreductase
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PDB id
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1cd2
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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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Ligand-Induced conformational changes in the crystal structures of pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.
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Authors
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V.Cody,
N.Galitsky,
D.Rak,
J.R.Luft,
W.Pangborn,
S.F.Queener.
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Ref.
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Biochemistry, 1999,
38,
4303-4312.
[DOI no: ]
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PubMed id
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Abstract
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Structural data from two independent crystal forms (P212121 and P21) of the
folate (FA) binary complex and from the ternary complex with the oxidized
coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase
(pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of
ligand-induced conformational changes in the structure of pcDHFR. These data are
also compared with the crystal structure of the ternary complex of methotrexate
(MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A
resolution. Comparison of the data for the FA binary complex of pcDHFR with
those for the ternary structures reveals significant differences, with a >7 A
movement of the loop region near residue 23 that results in a new "flap-open"
position for the binary complex, and a "closed" position in the ternary
complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In
the orthorhombic lattice for the binary FA pcDHFR complex, there is also an
unwinding of a short helical region near residue 47 that places hydrophobic
residues Phe-46 and Phe-49 toward the outer surface, a conformation that is
stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+
in the ternary folate pcDHFR complexes shows significant differences in
conformation compared with that observed in the MTX-NADPH-pcDHFR ternary
complex. Additionally, comparison of the conformations among these four pcDHFR
structures reveals evidence for subdomain movement that correlates with cofactor
binding states. The larger binding site access in the new "flap-open" loop 23
conformation of the binary FA complex is consistent with the rapid release of
cofactor from the product complex during catalysis as well as the more rapid
release of substrate product from the binary complex as a result of the weaker
contacts of the closed loop 23 conformation, compared to ecDHFR.
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Secondary reference #1
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Title
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Comparison of ternary complexes of pneumocystis carinii and wild-Type human dihydrofolate reductase with coenzyme NADPH and a novel classical antitumor furo[2,3-D]pyrimidine antifolate.
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Authors
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V.Cody,
N.Galitsky,
J.R.Luft,
W.Pangborn,
A.Gangjee,
R.Devraj,
S.F.Queener,
R.L.Blakley.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 1997,
53,
638-649.
[DOI no: ]
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PubMed id
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Figure 2.
Fig. 2. Schematic diagram of the DHFR inhibitors MTX, MTXO and
MTXT with numbering scheme.
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Figure 4.
Fig. 4. Superposition of the back-
bone trace of the pcDHFR (green)
ternary complex with MTXO and
NADPH (cyan) on that of hDHFR
(magenta) with the inhibitor com-
plex (gold). The diagram was
prepared using the program
SETOR
(Evans, 1993).
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The above figures are
reproduced from the cited reference
with permission from the IUCr
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Secondary reference #2
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Title
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Methotrexate-Resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, Crystallography, And potential as selectable markers.
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Authors
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W.S.Lewis,
V.Cody,
N.Galitsky,
J.R.Luft,
W.Pangborn,
S.K.Chunduru,
H.T.Spencer,
J.R.Appleman,
R.L.Blakley.
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Ref.
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J Biol Chem, 1995,
270,
5057-5064.
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PubMed id
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Secondary reference #3
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Title
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Methotrexate-Resistant variants of human dihydrofolate reductase. Effects of phe31 substitutions.
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Authors
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S.K.Chunduru,
V.Cody,
J.R.Luft,
W.Pangborn,
J.R.Appleman,
R.L.Blakley.
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Ref.
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J Biol Chem, 1994,
269,
9547-9555.
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PubMed id
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Secondary reference #4
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Title
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Crystal structure determination at 2.3 a of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-Gamma-Tetrazole.
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Authors
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V.Cody,
J.R.Luft,
E.Ciszak,
T.I.Kalman,
J.H.Freisheim.
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Ref.
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Anticancer Drug Des, 1992,
7,
483-491.
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PubMed id
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