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PDBsum entry 1pr5
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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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Structural basis for substrate specificity of escherichia coli purine nucleoside phosphorylase.
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Authors
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E.M.Bennett,
C.Li,
P.W.Allan,
W.B.Parker,
S.E.Ealick.
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Ref.
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J Biol Chem, 2003,
278,
47110-47118.
[DOI no: ]
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PubMed id
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Abstract
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Purine nucleoside phosphorylase catalyzes reversible phosphorolysis of purine
nucleosides and 2'-deoxypurine nucleosides to the free base and ribose (or
2'-deoxyribose) 1-phosphate. Whereas the human enzyme is specific for
6-oxopurine ribonucleosides, the Escherichia coli enzyme accepts additional
substrates including 6-oxopurine ribonucleosides, 6-aminopurine ribonucleosides,
and to a lesser extent purine arabinosides. These differences have been
exploited in a potential suicide gene therapy treatment for solid tumors. In an
effort to optimize this suicide gene therapy approach, we have determined the
three-dimensional structure of the E. coli enzyme in complex with 10 nucleoside
analogs and correlated the structures with kinetic measurements and computer
modeling. These studies explain the preference of the enzyme for ribose sugars,
show increased flexibility for active site residues Asp204 and Arg24, and
suggest that interactions involving the 1- and 6-positions of the purine and the
4'- and 5'-positions of the ribose provide the best opportunities to increase
prodrug specificity and enzyme efficiency.
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Figure 3.
FIG. 3. Schematic diagram showing key active site residues
and the contacts that are made with the substrates inosine and
phosphate. Dashed lines indicate hydrogen bonds (or partial
double bonds in carboxylate groups), and W indicates a water
molecule.
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Figure 7.
FIG. 7. Schematic diagrams of the two possible hydrogen
bonding schemes of the water channel near the purine N-1
position. A, hydrogen bonding scheme in which the first water
molecule is a donor to N-1 of 6-aminopurines (distances are from
the F-Ado A subunit). B, hydrogen bonding scheme in which the
first water molecule is an acceptor from N-1 of 6-oxopurines
(distances are from the Ino C subunit).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
47110-47118)
copyright 2003.
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