6b2q

Dual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosis

spinqualitylabelsall models 6b2q, resolution 2.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6b2q is a 4 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.88Å Ligands: 0BD, CJJ, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PKNA_MYCTU Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as FtsZ, Wag31, GlmU, FhaB, PstP, EmbR and Rv1422. Shows a strong preference for Thr versus Ser as the phosphoacceptor. Publication Abstract from PubMed Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki approximately 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 muM (1-2 mug/mL) against the H37Ra isolate of M. tuberculosis. Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions.,Wang T, Bemis G, Hanzelka B, Zuccola H, Wynn M, Moody CS, Green J, Locher C, Liu A, Gao H, Xu Y, Wang S, Wang J, Bennani YL, Thomson JA, Muh U ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi:, 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14. PMID:29259738 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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