 |
PDBsum entry 2prl
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase
|
PDB id
|
|
|
|
2prl
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites.
|
|
|
Authors
|
|
B.Walse,
V.T.Dufe,
B.Svensson,
I.Fritzson,
L.Dahlberg,
A.Khairoullina,
U.Wellmar,
S.Al-Karadaghi.
|
|
|
Ref.
|
|
Biochemistry, 2008,
47,
8929-8936.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
Inhibitors of dihydroorotate dehydrogenase (DHODH) have been suggested for the
treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, Plasmodium,
and bacterial and fungal infections. Here we present the structures of
N-terminally truncated (residues Met30-Arg396) DHODH in complex with two
inhibitors: a brequinar analogue (6) and a novel inhibitor (a fenamic acid
derivative) (7), as well as the first structure of the enzyme to be
characterized without any bound inhibitor. It is shown that 7 uses the
"standard" brequinar binding mode and, in addition, interacts with Tyr356, a
residue conserved in most class 2 DHODH proteins. Compared to the inhibitor-free
structure, some of the amino acid side chains in the tunnel in which brequinar
binds and which was suggested to be the binding site of ubiquinone undergo
changes in conformation upon inhibitor binding. Using our data, the loop regions
of residues Leu68-Arg72 and Asn212-Leu224, which were disordered in previously
studied human DHODH structures, could be built into the electron density. The
first of these loops, which is located at the entrance to the inhibitor-binding
pocket, shows different conformations in the three structures, suggesting that
it may interfere with inhibitor/cofactor binding. The second loop has been
suggested to control the access of dihydroorotate to the active site of the
enzyme and may be an important player in the enzymatic reaction. These
observations provide new insights into the dynamic features of the DHODH
reaction and suggest new approaches to the design of inhibitors against DHODH.
|
|
|
|
|
|
|
