3RAS

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

3RAS の概要

• エントリーDOI: 10.2210/pdb3ras/pdb
• 関連するPDBエントリー: 2JCV 2JCZ
• 分子名称: 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)
• 機能のキーワード: oxidoreductase, doxp/mep pathway, isoprene biosynthesis, 1-deoxy-d-xylulose 5-phosphate reductoisomerase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86467.18

構造登録者

Diao, J.,Deng, L.,Prasad, B.V.V.,Song, Y. (登録日: 2011-03-28, 公開日: 2011-05-25, 最終更新日: 2024-02-21)

主引用文献

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

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: 21561155
DOI: 10.1021/jm200363d

実験手法

X-RAY DIFFRACTION (2.55 Å)