5cqj

Crystal structure of E. coli undecaprenyl pyrophosphate synthase in complex with clomiphene

spinqualitylabelsall models 5cqj, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5cqj is a 2 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 53Q Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function UPPS_ECOLI Generates ditrans,octacis-undecaprenyl pyrophosphate (UPP) from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP). UPP is the precursor of glycosyl carrier lipid in the biosynthesis of bacterial cell wall polysaccharide components such as peptidoglycan and lipopolysaccharide. Publication Abstract from PubMed Drug combinations are valuable tools for studying biological systems. Although much attention has been given to synergistic interactions in revealing connections between cellular processes, antagonistic interactions can also have tremendous value in elucidating genetic networks and mechanisms of drug action. Here, we exploit the power of antagonism in a high-throughput screen for molecules that suppress the activity of targocil, an inhibitor of the wall teichoic acid (WTA) flippase in Staphylococcus aureus. Well-characterized antagonism within the WTA biosynthetic pathway indicated that early steps would be sensitive to this screen; however, broader interactions with cell wall biogenesis components suggested that it might capture additional targets. A chemical screening effort using this approach identified clomiphene, a widely used fertility drug, as one such compound. Mechanistic characterization revealed the target was the undecaprenyl diphosphate synthase, an enzyme that catalyzes the synthesis of a polyisoprenoid essential for both peptidoglycan and WTA synthesis. The work sheds light on mechanisms contributing to the observed suppressive interactions of clomiphene and in turn reveals aspects of the biology that underlie cell wall synthesis in S. aureus. Further, this effort highlights the utility of antagonistic interactions both in high-throughput screening and in compound mode of action studies. Importantly, clomiphene represents a lead for antibacterial drug discovery. Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase.,Farha MA, Czarny TL, Myers CL, Worrall LJ, French S, Conrady DG, Wang Y, Oldfield E, Strynadka NC, Brown ED Proc Natl Acad Sci U S A. 2015 Aug 17. pii: 201511751. PMID:26283394 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Undecaprenyl pyrophosphate synthase

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