4q9m

Crystal structure of UPPs in complex with FPP and an allosteric inhibitor

spinqualitylabelsall models 4q9m, resolution 2.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4q9m is a 2 chain structure with sequence from Streptococcus pneumoniae R6. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2ZW, CD, FPP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ISPT_STRR6 Catalyzes the condensation of isopentenyl diphosphate (IPP) with allylic pyrophosphates generating different type of terpenoids.[HAMAP-Rule:MF_01139] Publication Abstract from PubMed Undecaprenyl pyrophosphate synthase (UPPs) is an essential enzyme in a key bacterial cell wall synthesis pathway. It catalyzes the consecutive condensations of isopentenyl pyrophosphate (IPP) groups onto a trans-farnesyl pyrophosphate (FPP) to produce a C55 isoprenoid, undecaprenyl pyrophosphate (UPP). Here we report the discovery and co-crystal structures of a drug-like UPPs inhibitor in complex with Streptococcus pneumoniae UPPs, with and without substrate FPP, at resolutions of 2.2 and 2.1 A, respectively. The UPPs inhibitor has a low molecular weight (355 Da), but displays potent inhibition of UPP synthesis in vitro (IC50 50 nM) that translates into excellent whole cell antimicrobial activity against pathogenic strains of Streptococcal species (MIC90 0.4 mug/mL). Interestingly, the inhibitor does not compete with the substrates but rather binds at a site adjacent to the FPP binding site and interacts with the tail of the substrate. Based on the structures, an allosteric inhibition mechanism of UPPs is proposed for this inhibitor. This inhibition mechanism is supported by biochemical and biophysical experiments, and provides a basis for the development of novel antibiotics targeting Streptococcus pneumoniae. Discovery and structural characterization of an allosteric inhibitor of bacterial cis-prenyltransferase.,Danley DE, Baima ET, Mansour M, Fennell KF, Chrunyk BA, Mueller JP, Liu S, Qiu X Protein Sci. 2014 Oct 6. doi: 10.1002/pro.2579. PMID:25287857 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Inorganic pyrophosphatase 3D structures

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