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PDBsum entry 1js6
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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 insight into parkinson'S disease treatment from drug-Inhibited dopa decarboxylase.
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Authors
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P.Burkhard,
P.Dominici,
C.Borri-Voltattorni,
J.N.Jansonius,
V.N.Malashkevich.
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Ref.
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Nat Struct Biol, 2001,
8,
963-967.
[DOI no: ]
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PubMed id
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Abstract
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DOPA decarboxylase (DDC) is responsible for the synthesis of the key
neurotransmitters dopamine and serotonin via decarboxylation of
L-3,4-dihydroxyphenylalanine (L-DOPA) and L-5-hydroxytryptophan, respectively.
DDC has been implicated in a number of clinic disorders, including Parkinson's
disease and hypertension. Peripheral inhibitors of DDC are currently used to
treat these diseases. We present the crystal structures of ligand-free DDC and
its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to
the enzyme by forming a hydrazone linkage with the cofactor, and its catechol
ring is deeply buried in the active site cleft. The structures provide the
molecular basis for the development of new inhibitors of DDC with better
pharmacological characteristics.
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Figure 2.
Figure 2. Stereo view ribbon diagram of the polypeptide backbone
of DDC. The view is directly down the two-fold symmetry axis.
One monomer is completely red, whereas the other is green
(N-terminal domain), cyan (large domain) and blue (small
domain). The cofactors (PLP) and the inhibitors (carbiDOPA) are
shown in ball-and-stick representation in yellow. The N-terminal
domain of one monomer packs on top of the other monomer,
resulting in an extended dimer interface. The picture was drawn
with MOLSCRIPT50 and RASTER3D^51.
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Figure 3.
Figure 3. Active site cleft of DDC in complex with carbiDOPA.
a, Stereo view of the electron density of the inhibitor
carbiDOPA. The difference electron density (|F[o]| - |F[c]| map
with the inhibitor excluded from the phase calculation) in red,
contoured at 4  ,
is superimposed onto the inhibitor model. Nitrogen, phosphate
and oxygen atoms are marked blue, cyan and red, respectively.
Carbon atoms are colored in yellow for the enzyme, in magenta
for the PLP -carbiDOPA complex and in orange for the residues of
the other monomer. Hydrogen bonds are indicated in green dotted
lines. b, Detailed view of the hydrogen bond interactions,
including all structural water molecules in the active site.
Color code as in (a). c, A model of modified carbiDOPA with an
additional 2' hydroxyl group (cyan). The newly established
hydrogen bonds to the structural water molecules and the
hydrazone nitrogen are indicated as dotted lines (cyan).
Otherwise, the color code is as in (a). The picture was drawn
with MOLSCRIPT50 and RASTER3D^51.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2001,
8,
963-967)
copyright 2001.
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Secondary reference #1
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Title
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Preliminary X-Ray analysis of a new crystal form of recombinant pig kidney dopa decarboxylase.
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Authors
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V.N.Malashkevich,
P.Burkhard,
P.Dominici,
P.S.Moore,
C.Borri voltattorni,
J.N.Jansonius.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 1999,
55,
568-570.
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PubMed id
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Secondary reference #2
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Title
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Crystallization and preliminary X-Ray analysis of pig kidney dopa decarboxylase.
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Authors
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V.N.Malashkevich,
P.Filipponi,
U.Sauder,
P.Dominici,
J.N.Jansonius,
C.Borri voltattorni.
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Ref.
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J Mol Biol, 1992,
224,
1167-1170.
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PubMed id
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