Structural highlights
FunctionISPE_KLEP7 Catalyzes the phosphorylation of the position 2 hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol. Publication Abstract from PubMedEnzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here, we focus on 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from pathogenic microorganisms; Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. We determined the X-ray crystal structures of IspE-inhibitor complexes and studied inhibitors' binding modes targeting the substrate pocket. The experimental results indicate the need for distinct inhibitor strategies due to structural differences among IspE homologs, particularly for A. baumannii IspE, which displays a unique inhibitory profile due to a tighter hydrophobic subpocket in the substrate binding site. This study enhances our understanding of the MEP enzymes and sets the stage for structure-based drug design of selective inhibitors to combat pathogenic microorganisms. IspE kinase as an anti-infective target: Role of a hydrophobic pocket in inhibitor binding.,Hamid R, Walsh DJ, Diamanti E, Aguilar D, Lacour A, Hamed MM, Hirsch AKH Structure. 2024 Dec 5;32(12):2390-2398.e2. doi: 10.1016/j.str.2024.10.009. Epub , 2024 Nov 6. PMID:39510075[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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