3RAS
Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) complexed with a lipophilic phosphonate inhibitor
Summary for 3RAS
| Entry DOI | 10.2210/pdb3ras/pdb |
| Related | 2JCV 2JCZ |
| Descriptor | 1-deoxy-D-xylulose 5-phosphate reductoisomerase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-(N-HYDROXYACETAMIDO)-1-(3,4-DICHLOROPHENYL)PROPYLPHOSPHONIC ACID, ... (7 entities in total) |
| Functional Keywords | oxidoreductase, doxp/mep pathway, isoprene biosynthesis, 1-deoxy-d-xylulose 5-phosphate reductoisomerase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 86467.18 |
| Authors | Diao, J.,Deng, L.,Prasad, B.V.V.,Song, Y. (deposition date: 2011-03-28, release date: 2011-05-25, Last modification date: 2024-02-21) |
| Primary citation | Deng, L.,Diao, J.,Chen, P.,Pujari, V.,Yao, Y.,Cheng, G.,Crick, D.C.,Prasad, B.V.,Song, Y. Inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase by lipophilic phosphonates: SAR, QSAR, and crystallographic studies. J.Med.Chem., 54:4721-4734, 2011 Cited by PubMed Abstract: 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) is a novel target for developing new antibacterial (including antituberculosis) and antimalaria drugs. Forty-one 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 K(i) 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 performed well, 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. PubMed: 21561155DOI: 10.1021/jm200363d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.55 Å) |
Structure validation
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