5u94

Crystal structure of the Mycobacterium tuberculosis PASTA kinase PknB in complex with the potential theraputic kinase inhibitor GSK690693.

spinqualitylabelsall models 5u94, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5u94 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: G93, GOL, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PKNB_MYCTU Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as GarA, GlmU, PapA5, PbpA, FhaB (Rv0019c), FhaA (Rv0020c), MviN, PstP, EmbR, Rv1422, Rv1747 and RseA. Shows a strong preference for Thr versus Ser as the phosphoacceptor. Publication Abstract from PubMed New tools and concepts are needed to combat antimicrobial resistance. Actinomycetes and firmicutes share several eukaryotic-like Ser/Thr kinases (eSTK) that offer antibiotic development opportunities, including PknB, an essential mycobacterial eSTK. Despite successful development of potent biochemical PknB inhibitors by many groups, clinically useful microbiologic activity has been elusive. Additionally, PknB kinetics are not fully described, nor are structures with specific inhibitors available to inform inhibitor design. We used computational modeling with available structural information to identify human kinase inhibitors predicted to bind PknB, and we selected hits based on drug-like characteristics intended to increase the likelihood of cell entry. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We performed an in-depth characterization of PknB and found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel X-ray structure confirmed that the inhibitors bound as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity toward mycobacteria and nocardia. We demonstrated that the inhibitors are uniquely potentiated by beta-lactams but not antibiotics traditionally used to treat mycobacteria, consistent with PknB's role in sensing cell wall stress. This is the first demonstration in the phylum actinobacteria that some beta-lactam antibiotics could be more effective if paired with a PknB inhibitor. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can act with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options. In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with beta-Lactams To Inhibit Mycobacterial Growth.,Wlodarchak N, Teachout N, Beczkiewicz J, Procknow R, Schaenzer AJ, Satyshur K, Pavelka M, Zuercher W, Drewry D, Sauer JD, Striker R Mol Pharm. 2018 Nov 5;15(11):5410-5426. doi: 10.1021/acs.molpharmaceut.8b00905., Epub 2018 Oct 18. PMID:30285456 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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