PDBsum entry 1d3h

Oxidoreductase

PDB id: 1d3h

Contents

Protein chain

364 a.a. *

Ligands

SO4

ACT

A26

FMN

ORO

Waters ×298

* Residue conservation analysis

PDB id:

1d3h

Name:

Oxidoreductase

Title:

Human dihydroorotate dehydrogenase complexed with antiproliferative agent a771726

Structure:

Dihydroorotate dehydrogenase. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

1.80Å R-factor: 0.162 R-free: 0.185

Authors:

S.Liu,E.A.Neidhardt,T.H.Grossman,T.Ocain,J.Clardy

Key ref:

S.Liu et al. (2000). Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure Fold Des, 8, 25-33. PubMed id: 10673429 DOI: 10.1016/S0969-2126(00)00077-0

Date:

29-Sep-99 Release date: 13-Aug-00

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: 10.1016/S0969-2126(00)00077-0

Structure Fold Des 8:25-33 (2000)

PubMed id: 10673429

Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents.

S.Liu, E.A.Neidhardt, T.H.Grossman, T.Ocain, J.Clardy.

ABSTRACT

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.

Selected figure(s)

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].

The above figure is reprinted by permission from Cell Press: Structure Fold Des (2000, 8, 25-33) copyright 2000.

Figure was selected by an automated process.