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PDBsum entry 1d3h
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Oxidoreductase
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PDB id
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1d3h
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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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Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents.
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Authors
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S.Liu,
E.A.Neidhardt,
T.H.Grossman,
T.Ocain,
J.Clardy.
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Ref.
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Structure Fold Des, 2000,
8,
25-33.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth committed
step in the de novo biosynthesis of pyrimidines. As rapidly proliferating human
T cells have an exceptional requirement for de novo pyrimidine biosynthesis,
small molecule DHODH inhibitors constitute an attractive therapeutic approach to
autoimmune diseases, immunosuppression, and cancer. Neither the structure of
human DHODH nor any member of its family was known. RESULTS: The high-resolution
crystal structures of human DHODH in complex with two different inhibitors have
been solved. The initial set of phases was obtained using multiwavelength
anomalous diffraction phasing with selenomethionine-containing DHODH. The
structures have been refined to crystallographic R factors of 16.8% and 16.2% at
resolutions of 1. 6 A and 1.8 A for inhibitors related to brequinar and
leflunomide, respectively. CONCLUSIONS: Human DHODH has two domains: an
alpha/beta-barrel domain containing the active site and an alpha-helical domain
that forms the opening of a tunnel leading to the active site. Both inhibitors
share a common binding site in this tunnel, and differences in the binding
region govern drug sensitivity or resistance. The active site of human DHODH is
generally similar to that of the previously reported bacterial active site. The
greatest differences are that the catalytic base removing the proton from
dihydroorotate is a serine rather than a cysteine, and that packing of the
flavin mononucleotide in its binding site is tighter.
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Figure 5.
Figure 5. Binding of A771726 in the hydrophobic channel of
human DHODH. (a) Stereoview of the binding interactions of
A771726. Ligands are shown in ball-and-stick representation, and
residues interacting with A771726 are represented by thin
sticks. Hydrogen bonds are shown as dashed black lines. (b) A
2F[o]-F[c ]electron-density map of A771726, FMN and orotate
contoured at 1.2s (1.8 Å). Ligands and selected DHODH residues
in the vicinity are shown in ball-and-stick representation. This
figure was prepared with MOLSCRIPT [34].
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The above figure is
reprinted
by permission from Cell Press:
Structure Fold Des
(2000,
8,
25-33)
copyright 2000.
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