2PRH

The structures of apo- and inhibitor bound human dihydroorotate dehydrogenase reveal conformational flexibility within the inhibitor binding site

2PRH の概要

• エントリーDOI: 10.2210/pdb2prh/pdb
• 関連するPDBエントリー: 1D3G 2PRL 2PRM
• 分子名称: Dihydroorotate dehydrogenase, mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (6 entities in total)
• 機能のキーワード: protein inhibitor complex, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion inner membrane ; Single-pass membrane protein : Q02127
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41062.15

構造登録者

Walse, B.,Dufe, V.T.,Al-Karadaghi, S. (登録日: 2007-05-04, 公開日: 2008-05-20, 最終更新日: 2023-08-30)

主引用文献

Walse, B.,Dufe, V.T.,Svensson, B.,Fritzson, I.,Dahlberg, L.,Khairoullina, A.,Wellmar, U.,Al-Karadaghi, S.
The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites
Biochemistry, 47:8929-8936, 2008

PubMed 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.

PubMed: 18672895
DOI: 10.1021/bi8003318

実験手法

X-RAY DIFFRACTION (2.4 Å)