PDBsum entry 2fpy

Oxidoreductase

PDB id: 2fpy

Contents

Protein chain

364 a.a. *

Ligands

ACT

SO4 ×5

FMN

ORO

ILF

Waters ×291

* Residue conservation analysis

PDB id:

2fpy

Name:

Oxidoreductase

Title:

Dual binding mode of a novel series of dhodh inhibitors

Structure:

Dihydroorotate dehydrogenase, mitochondrial precursor. Chain: a. Synonym: dihydroorotate oxidase, dhodehase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dhodh. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.181 R-free: 0.200

Authors:

R.Baumgartner,J.Leban

Key ref:

R.Baumgartner et al. (2006). Dual binding mode of a novel series of DHODH inhibitors. J Med Chem, 49, 1239-1247. PubMed id: 16480261 DOI: 10.1021/jm0506975

Date:

17-Jan-06 Release date: 23-Jan-07

Protein chain

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

Seq: 395 a.a.

Struc: 364 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

DOI no: 10.1021/jm0506975

J Med Chem 49:1239-1247 (2006)

PubMed id: 16480261

Dual binding mode of a novel series of DHODH inhibitors.

R.Baumgartner, M.Walloschek, M.Kralik, A.Gotschlich, S.Tasler, J.Mies, J.Leban.

ABSTRACT

Human dihydroorotate dehydrogenase (DHODH) represents an important target for the treatment of hyperproliferative and inflammatory diseases. In the cell DHODH catalyzes the rate-limiting step of the de novo pyrimidine biosynthesis. DHODH inhibition results in beneficial immunosuppressant and antiproliferative effects in diseases such as rheumatoid arthritis. Here, we present high-resolution X-ray structures of human DHODH in complex with a novel class of low molecular weight compounds that inhibit the enzyme in the nanomolar range. Some compounds showed an interesting dual binding mode within the same cocrystal strongly depending on the nature of chemical substitution. Measured in vitro activity data correlated with the prevailing mode of binding and explained the observed structure-activity relationship. Additionally, the X-ray data confirmed the competitive nature of the inhibitors toward the putative ubiquinone binding site and will guide structure-based design and synthesis of molecules with higher activity.