3ANM

Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) complexed with 5-phenylpyridin-2-ylmethylphosphonic acid

Summary for 3ANM

• Entry DOI: 10.2210/pdb3anm/pdb
• Related: 1JVS 1T1R 1T1S 2EGH 3ANL 3ANN
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, [(5-phenylpyridin-2-yl)methyl]phosphonic acid, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: reductoisomerase, nadph binding, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 93482.00

Authors

Endo, K.,Kato, M.,Deng, L.,Song, Y.,Yajima, S. (deposition date: 2010-09-03, release date: 2011-02-23, Last modification date: 2023-11-01)

Primary citation

Deng, L.,Endo, K.,Kato, M.,Cheng, G.,Yajima, S.,Song, Y.
Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes
ACS Med Chem Lett, 2:165-170, 2011

PubMed Abstract: Fosmidomycin, a potent inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), has antibacterial and antimalaria activity. Due to its poor pharmacokinetics, more lipophilic DXR inhibitors are needed. However, the hydrophobic binding site(s) in DXR remains elusive. Here, pyridine/quinoline containing phosphonates are identified to be DXR inhibitors with IC(50) values as low as 840 nM. We also report three DXR:inhibitor structures, revealing a novel binding mode. The indole group of Trp211 is found to move ~4.6 Å to open up a mainly hydrophobic pocket, where the pyridine/quinoline rings of the inhibitors are located and have strong π-π stacking/charge-transfer interactions with the indole. Docking studies demonstrate our structures could be used to predict the binding modes of other lipophilic DXR inhibitors. Overall, this work shows an important role of Trp211 in inhibitor recognition and provides a structural basis for future drug design and development.

PubMed: 21379374
DOI: 10.1021/ml100243r

Experimental method

X-RAY DIFFRACTION (2 Å)