5IQG

Aminoglycoside Phosphotransferase (2'')-Ia (CTD of AAC(6')-Ie/APH(2'')-Ia) in complex with GDP, Magnesium, and Gentamicin C1

Summary for 5IQG

• Entry DOI: 10.2210/pdb5iqg/pdb
• Related: 5BYL 5IQA 5IQB 5IQC 5IQD 5IQE 5IQF 5IQH 5IQI
• Descriptor: Bifunctional AAC/APH, GUANOSINE-5'-DIPHOSPHATE, gentamicin C1, ... (6 entities in total)
• Functional Keywords: kinase, antibiotic, aminoglycoside, resistance, transferase
• Biological source: Staphylococcus aureus
• Cellular location: Cytoplasm: P0A0C1
• Total number of polymer chains: 4
• Total formula weight: 147776.78

Authors

Caldwell, S.J.,Berghuis, A.M. (deposition date: 2016-03-10, release date: 2016-05-25, Last modification date: 2023-09-27)

Primary citation

Caldwell, S.J.,Huang, Y.,Berghuis, A.M.
Antibiotic Binding Drives Catalytic Activation of Aminoglycoside Kinase APH(2)-Ia.
Structure, 24:935-945, 2016

PubMed Abstract: APH(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.

PubMed: 27161980
DOI: 10.1016/j.str.2016.04.002

Experimental method

X-RAY DIFFRACTION (2.5 Å)