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|3ras, resolution 2.55Å ()|
|Ligands:||, , , ,|
|Gene:||dxr, Rv2870c, MT2938, MTCY274.01c (Mycobacterium tuberculosis)|
Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) complexed with a lipophilic phosphonate inhibitor
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.