3q2j

Crystal Structure of 3',5"-Aminoglycoside Phosphotransferase Type IIIa Protein Kinase Inhibitor CKI-7 Complex

spinqualitylabelsall models 3q2j, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3q2j is a 2 chain structure with sequence from Enterococcus faecalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, CKI Related: 1j7l, 1j7i, 1j7u, 1l8t, 2b0q, 3h8p Activity: Kanamycin kinase, with EC number 2.7.1.95 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3')-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3')-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eukaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides. Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.,Fong DH, Xiong B, Hwang J, Berghuis AM PLoS One. 2011 May 9;6(5):e19589. doi: 10.1371/journal.pone.0019589. PMID:21573013 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphotransferase

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