4GAE

Crystal structure of plasmodium dxr in complex with a pyridine-containing inhibitor

Summary for 4GAE

• Entry DOI: 10.2210/pdb4gae/pdb
• Related: 3AU9
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, [(1R)-3-[acetyl(hydroxy)amino]-1-(pyridin-4-yl)propyl]phosphonic acid, ... (9 entities in total)
• Functional Keywords: nadph binding, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Plasmodium falciparum
• Cellular location: Plastid, apicoplast: O96693
• Total number of polymer chains: 2
• Total formula weight: 100224.87

Authors

Diao, J.,Xue, J.,Cai, G.,Deng, L.,Song, Y. (deposition date: 2012-07-25, release date: 2013-02-06, Last modification date: 2023-09-13)

Primary citation

Xue, J.,Diao, J.,Cai, G.,Deng, L.,Zheng, B.,Yao, Y.,Song, Y.
Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.
ACS Med Chem Lett, 4:278-282, 2013

PubMed Abstract: 1-Deoxy--xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors of DXR (DXR) having K values of 1.9 - 13 nM, with the best one being ~11× more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant with EC values as low as 170 nM. A 2.3 Å crystal structure of DXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and DXR account for the enhanced activity.

PubMed: 23795240
DOI: 10.1021/ml300419r

Experimental method

X-RAY DIFFRACTION (2.3 Å)