2Y1C: X-Ray Structure Of 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase, Dxr, Rv2870c, From Mycobacterium Tuberculosis, In Complex With Manganese

Citation:
Abstract
The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 muM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mug/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.
PDB ID: 2Y1CDownload
MMDB ID: 91699
PDB Deposition Date: 2010/12/8
Updated in MMDB: 2011/08
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 2Y1C: dimeric; determined by author and by software (PISA)
Molecular Components in 2Y1C
Label Count Molecule
Proteins (2 molecules)
2
1-deoxy-d-xylulose 5-phosphate Reductoisomerase
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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