PDBsum entry 2prl

Oxidoreductase

PDB id: 2prl

Contents

Protein chain

367 a.a. *

Ligands

SO4

ACT ×2

FMN

ORO

R2C

DDQ

Waters ×231

* Residue conservation analysis

PDB id:

2prl

Name:

Oxidoreductase

Title:

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

Structure:

Dihydroorotate dehydrogenase, mitochondrial. Chain: a. Synonym: (dihydroorotate oxidase. Dhodehase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: mitochondria. Gene: dhodh. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.169 R-free: 0.194

Authors:

B.Walse,V.T.Dufe,S.Al-Karadaghi

Key ref:

B.Walse et al. (2008). The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites. Biochemistry, 47, 8929-8936. PubMed id: 18672895

Date:

04-May-07 Release date: 20-May-08

Protein chain

Q02127  (PYRD_HUMAN) -  Dihydroorotate dehydrogenase (quinone), mitochondrial from Homo sapiens

Seq: 395 a.a.

Struc: 367 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.5.2 - dihydroorotate dehydrogenase (quinone).
• Reaction: (S)-dihydroorotate + a quinone = orotate + a quinol

(S)-dihydroorotate (Bound ligand (Het Group name = ORO) corresponds exactly) + quinone = orotate + quinol

• Cofactor: FMN

FMN (Bound ligand (Het Group name = FMN) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Biochemistry 47:8929-8936 (2008)

PubMed id: 18672895

The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites.

B.Walse, V.T.Dufe, B.Svensson, I.Fritzson, L.Dahlberg, A.Khairoullina, U.Wellmar, S.Al-Karadaghi.

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.