4gkh

Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor 1-NA-PP1

spinqualitylabelsall models 4gkh, resolution 1.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4gkh is a 12 chain structure with sequence from Acinetobacter baumannii AYE. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.863Å Ligands: 0J9, ACT, CL, KAN, MSE, NA, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Activity of the aminoglycoside phosphotransferase APH(3')-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescuing compromised antibiotics such as aminoglycosides is targeting the enzymes conferring resistance with small molecules. Previously we demonstrated that eukaryotic protein kinase (ePK) inhibitors could inhibit APH enzymes, due to the structural similarity between these two enzyme families. However, limited structural information of enzyme-inhibitor complexes hindered interpretation of the results. As well, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. Here, we structurally and functionally characterize inhibition of APH(3')-Ia by three diverse chemical scaffolds - anthrapyrazolone, 4-anilinoquinazoline and pyrazolopyrimidine (PP) - and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3')-Ia versus ePKs. Using this observation, we identify PP-derivatives that select against ePKs, attenuate APH(3')-Ia activity and rescue aminoglycoside antibiotic activity against a resistant E. coli strain. The structures presented here and these inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance. Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance.,Stogios PJ, Spanogiannopoulos P, Evdokimova E, Egorova O, Shakya T, Todorovic N, Capretta A, Wright GD, Savchenko A Biochem J. 2013 Jun 12. PMID:23758273 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphotransferase 3D structures

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