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3ras

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3ras, resolution 2.55Å ()
Ligands: , , , ,
Gene: dxr, Rv2870c, MT2938, MTCY274.01c (Mycobacterium tuberculosis)
Activity: 1-deoxy-D-xylulose-5-phosphate reductoisomerase, with EC number 1.1.1.267
Related: 2jcz, 2jcv


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) complexed with a lipophilic phosphonate inhibitor

Publication Abstract from PubMed

1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including anti-tuberculosis) and antimalaria drugs. 41 lipophilic phosphonates, representing a new class of DXR inhibitors, were synthesized, among which 5-phenylpyridin-2-ylmethylphosphonic acid possesses the most activity against E. coli DXR (EcDXR) with a Ki of 420 nM. Structure activity relationships (SAR) are discussed, which can be rationalized using our EcDXR:inhibitor structures, and a predictive quantitative SAR (QSAR) model is also developed. Since inhibition studies of DXR from Mycobacterium tuberculosis (MtDXR) have not been well performed, 48 EcDXR inhibitors with a broad chemical diversity were found, however, to generally exhibit considerably reduced activity against MtDXR. The crystal structure of a MtDXR:inhibitor complex reveals the flexible loop containing the residues 198-208 has no strong interactions with the 3,4-dichlorophenyl group of the inhibitor, representing a structural basis for the reduced activity. Overall, these results provide implications in the future design and development of potent DXR inhibitors.

Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR and Crystallographic Studies., Deng L, Diao J, Chen P, Pujari V, Yao Y, Cheng G, Crick DC, Prasad BV, Song Y, J Med Chem. 2011 May 11. PMID:21561155

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

3ras is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.

Reference

  • Deng L, Diao J, Chen P, Pujari V, Yao Y, Cheng G, Crick DC, Prasad BV, Song Y. Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase by Lipophilic Phosphonates: SAR, QSAR and Crystallographic Studies. J Med Chem. 2011 May 11. PMID:21561155 doi:10.1021/jm200363d

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