4AIC

X-ray structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR, Rv2870c, from Mycobacterium tuberculosis, in complex with fosmidomycin, manganese and NADPH

Replaces:  2JCZ

Summary for 4AIC

• Entry DOI: 10.2210/pdb4aic/pdb
• Related: 2C82 2JCV 2JCX 2JCY 2JD0 2JD1 2JD2 2Y1C 2Y1D 2Y1E 2Y1F 2Y1G 4A03
• Descriptor: 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, 3-[FORMYL(HYDROXY)AMINO]PROPYLPHOSPHONIC ACID, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: oxidoreductase, doxp/mep pathway
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 85377.89

Authors

Henriksson, L.M.,Unge, T.,Jones, T.A.,Mowbray, S.L. (deposition date: 2012-02-09, release date: 2012-02-22, Last modification date: 2023-12-20)

Primary citation

Henriksson, L.M.,Unge, T.,Carlsson, J.,Aqvist, J.,Mowbray, S.L.,Jones, T.A.
Structures of Mycobacterium Tuberculosis 1-Deoxy-D-Xylulose- 5-Phosphate Reductoisomerase Provide New Insights Into Catalysis.
J.Biol.Chem., 282:19905-, 2007

PubMed Abstract: Isopentenyl diphosphate is the precursor of various isoprenoids that are essential to all living organisms. It is produced by the mevalonate pathway in humans but by an alternate route in plants, protozoa, and many bacteria. 1-deoxy-D-xylulose-5-phosphate reductoisomerase catalyzes the second step of this non-mevalonate pathway, which involves an NADPH-dependent rearrangement and reduction of 1-deoxy-D-xylulose 5-phosphate to form 2-C-methyl-D-erythritol 4-phosphate. The use of different pathways, combined with the reported essentiality of the enzyme makes the reductoisomerase a highly promising target for drug design. Here we present several high resolution structures of the Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase, representing both wild type and mutant enzyme in various complexes with Mn(2+), NADPH, and the known inhibitor fosmidomycin. The asymmetric unit corresponds to the biological homodimer. Although crystal contacts stabilize an open active site in the B molecule, the A molecule displays a closed conformation, with some differences depending on the ligands bound. An inhibition study with fosmidomycin resulted in an estimated IC(50) value of 80 nm. The double mutant enzyme (D151N/E222Q) has lost its ability to bind the metal and, thereby, also its activity. Our structural information complemented with molecular dynamics simulations and free energy calculations provides the framework for the design of new inhibitors and gives new insights into the reaction mechanism. The conformation of fosmidomycin bound to the metal ion is different from that reported in a previously published structure and indicates that a rearrangement of the intermediate is not required during catalysis.

PubMed: 17491006
DOI: 10.1074/JBC.M701935200

Experimental method

X-RAY DIFFRACTION (2.05 Å)