PDBsum entry 1q0h

Oxidoreductase

PDB id: 1q0h

Contents

Protein chain

398 a.a. *

Ligands

FOM

NDP

CIT

Waters ×266

* Residue conservation analysis

PDB id:

1q0h

Name:

Oxidoreductase

Title:

Crystal structure of selenomethionine-labelled dxr in complex with fosmidomycin

Structure:

1-deoxy-d-xylulose 5-phosphate reductoisomerase. Chain: a. Synonym: dxp reductoisomerase, 1-deoxyxylulose-5-phosphate reductoisomerase, ispc. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Gene: dxr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.20Å R-factor: 0.189 R-free: 0.212

Authors:

A.Mac Sweeney,R.Lange,A.D'Arcy,A.Douangamath,J.-P.Surivet,C.Oefner

Key ref:

A.Mac Sweeney et al. (2005). The crystal structure of E.coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-binding closed enzyme conformation. J Mol Biol, 345, 115-127. PubMed id: 15567415 DOI: 10.1016/j.jmb.2004.10.030

Date:

16-Jul-03 Release date: 20-Jul-04

Protein chain

P45568  (DXR_ECOLI) -  1-deoxy-D-xylulose 5-phosphate reductoisomerase from Escherichia coli (strain K12)

Seq: 398 a.a.

Struc: 398 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.267 - 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
• Reaction: 2-C-methyl-D-erythritol 4-phosphate + NADP⁺ = 1-deoxy-D-xylulose 5-phosphate + NADPH + H⁺

2-C-methyl-D-erythritol 4-phosphate (Bound ligand (Het Group name = CIT) matches with 44.44% similarity) + NADP(+) (Bound ligand (Het Group name = NDP) matches with 64.58% similarity) = 1-deoxy-D-xylulose 5-phosphate + NADPH + H(+)

• Cofactor: Mg(2+) or cobalt cation or Mn(2+)

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

reference

DOI no: 10.1016/j.jmb.2004.10.030

J Mol Biol 345:115-127 (2005)

PubMed id: 15567415

The crystal structure of E.coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase in a ternary complex with the antimalarial compound fosmidomycin and NADPH reveals a tight-binding closed enzyme conformation.

A.Mac Sweeney, R.Lange, R.P.Fernandes, H.Schulz, G.E.Dale, A.Douangamath, P.J.Proteau, C.Oefner.

ABSTRACT

The key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) has been shown to be the target enzyme of fosmidomycin, an antimalarial, antibacterial and herbicidal compound. Here we report the crystal structure of selenomethionine-labelled Escherichia coli DXR in a ternary complex with NADPH and fosmidomycin at 2.2 A resolution. The structure reveals a considerable conformational rearrangement upon fosmidomycin binding and provides insights into the slow, tight binding inhibition mode of the inhibitor. Although the inhibitor displays an unusual non-metal mediated mode of inhibition, which is an artefact most likely due to the low metal affinity of DXR at the pH used for crystallization, the structural data add valuable information for the rational design of novel DXR inhibitors. Using this structure together with the published structural data and the 1.9 A crystal structure of DXR in a ternary complex with NADPH and the substrate 1-deoxy-D-xylulose 5-phosphate, a model for the physiologically relevant tight-binding mode of inhibition is proposed. The structure of the substrate complex must be interpreted with caution due to the presence of a second diastereomer in the active site.

Selected figure(s)

Figure 6.
Figure 6. (A) An FoKFc omit electron density map of fosmidomycin in the active site of DXR, contoured at 3s. Met276 is shown in orange on the left and Met214 is shown in two conformations: that of SeMet214 in magenta (right) and that of wild-type Met214 in orange (left). (B) Hydrogen bonding interactions of the inhibitor fosmidomycin in the active site of DXR. (C) A schematic diagram of fosmidomycin binding to SeMet-labelled DXR.

Figure 7.
Figure 7. (A) An FoKFc omit electron density map of the substrate DXP in the active site of DXR, contoured at 3s. The position of the hydroxyl group in the L-configuration at C4 is depicted in green. (B) Hydrogen bonding interactions of the substrate DXP in the active site of DXR. The position of the hydroxyl group in the L-configuration at C4 is depicted in green. (C) A schematic diagram of the substrate DXP binding to DXR. For clarity, the bond between the carboxylate of E231 and the hydroxyl group of C4 of DXP has been omitted.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 345, 115-127) copyright 2005.

Figures were selected by an automated process.