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PDBsum entry 1w4r
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Contents |
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174 a.a.
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(+ 0 more)
160 a.a.
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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 of a type ii thymidine kinase with bound dttp.
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Authors
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M.S.Birringer,
M.T.Claus,
G.Folkers,
D.P.Kloer,
G.E.Schulz,
L.Scapozza.
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Ref.
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FEBS Lett, 2005,
579,
1376-1382.
[DOI no: ]
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PubMed id
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Abstract
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The structure of human cytosolic thymidine kinase in complex with its feedback
inhibitor 2'-deoxythymidine-5'-triphosphate was determined. This structure is
the first representative of the type II thymidine kinases found in several
pathogens. The structure deviates strongly from the known structures of type I
thymidine kinases such as the Herpes simplex enzyme. It contains a zinc-binding
domain with four cysteines complexing a structural zinc ion. Interestingly, the
backbone atoms of the type II enzyme bind thymine via hydrogen-bonds, in
contrast to type I, where side chains are involved. This results in a
specificity difference exploited for antiviral therapy. The presented structure
will foster the development of new drugs and prodrugs for numerous therapeutic
applications.
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Figure 3.
Fig. 3. Stereoview of the active center of hTK1. Water
molecules are red balls, hydrogen bonds are dashed lines. (A)
Bound feedback inhibitor dTTP with hydrogen bonding network. The
conformation of dTTP in its two binding modes was derived from
the F[o]–F[c] omit electron density map here contoured at 3σ
(green). The 40% binding mode is shown in a semi transparent
mode. (B) The nucleotide is bound by the tight interactions with
protein residues. Hydrogen bonds to main chain atoms and
stacking of the pyrimidine ring between Phe101, Phe133 and
Tyr181 are responsible for the high substrate specificity.
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Figure 4.
Fig. 4. B-factor plot of the eight subunits of the reported
hTK1 structure. The map correlation is depicted on the right
side of the diagram. High mobility of some residues leads to
lacking parts in the structure. The line on top shows the
secondary structure assignment as given by the program DSSP
[20]. The β-sheets and helices are displayed as arrows and
tubes, respectively and labeled.
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The above figures are
reprinted
by permission from the Federation of European Biochemical Societies:
FEBS Lett
(2005,
579,
1376-1382)
copyright 2005.
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