5iqi
From Proteopedia
Aminoglycoside Phosphotransferase (2)-Ia (CTD of AAC(6')-Ie/APH(2)-Ia) Y237F mutant in complex with GMPPNP and Magnesium
Structural highlights
FunctionAACA_STAAU Resistance to gentamicin, tobramycin, and kanamycin. Tobramycin and kanamycin resistance is due to the ACC activity, specified by N-terminal region, and the gentamicin resistance is due to the APH activity encoded by the C-terminal region of the protein. Publication Abstract from PubMedAPH(2)-Ia is a widely disseminated resistance factor frequently found in clinical isolates of Staphylococcus aureus and pathogenic enterococci, where it is constitutively expressed. APH(2)-Ia confers high-level resistance to gentamicin and related aminoglycosides through phosphorylation of the antibiotic using guanosine triphosphate (GTP) as phosphate donor. We have determined crystal structures of the APH(2)-Ia in complex with GTP analogs, guanosine diphosphate, and aminoglycosides. These structures collectively demonstrate that aminoglycoside binding to the GTP-bound kinase drives conformational changes that bring distant regions of the protein into contact. These changes in turn drive a switch of the triphosphate cofactor from an inactive, stabilized conformation to a catalytically competent active conformation. This switch has not been previously reported for antibiotic kinases or for the structurally related eukaryotic protein kinases. This catalytic triphosphate switch presents a means by which the enzyme can curtail wasteful hydrolysis of GTP in the absence of aminoglycosides, providing an evolutionary advantage to this enzyme. Antibiotic Binding Drives Catalytic Activation of Aminoglycoside Kinase APH(2)-Ia.,Caldwell SJ, Huang Y, Berghuis AM Structure. 2016 May 5. pii: S0969-2126(16)30038-7. doi:, 10.1016/j.str.2016.04.002. PMID:27161980[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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