2vf3
Aquifex aeolicus IspE in complex with ligand
Structural highlights
FunctionISPE_AQUAE Catalyzes the phosphorylation of the position 2 hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.[HAMAP-Rule:MF_00061] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedEnzymes of the non-mevalonate pathway for isoprenoid biosynthesis are therapeutic targets for the treatment of important infectious diseases. Whereas this pathway is absent in humans, it is used by plants, many eubacteria and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis. Herein, we report on the design, preparation and biological evaluation of a new series of ligands for IspE protein, a kinase from this pathway. These inhibitors were developed for the inhibition of IspE from Escherichia coli, using structure-based design approaches. Structure-activity relationships (SARs) and a co-crystal structure of Aquifex aeolicus IspE bound to a representative inhibitor validate the proposed binding mode. The crystal structure shows that the ligand binds in the substrate-rather than the adenosine 5'-triphosphate (ATP)-binding pocket. As predicted, a cyclopropyl substituent occupies a small cavity not used by the substrate. The optimal volume occupancy of this cavity is explored in detail. In the co-crystal structure, a diphosphate anion binds to the Gly-rich loop, which normally accepts the triphosphate moiety of ATP. This structure provides useful insights for future structure-based developments of inhibitors for the parasite enzymes. Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis.,Hirsch AK, Alphey MS, Lauw S, Seet M, Barandun L, Eisenreich W, Rohdich F, Hunter WN, Bacher A, Diederich F Org Biomol Chem. 2008 Aug 7;6(15):2719-30. Epub 2008 Jun 2. PMID:18633530[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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