3Q2M

Crystal Structure of Spectinomycin Phosphotransferase, APH(9)-Ia, Protein Kinase Inhibitor CKI-7 Complex

Summary for 3Q2M

• Entry DOI: 10.2210/pdb3q2m/pdb
• Related: 3I0O 3I0Q 3I1A
• Descriptor: Spectinomycin phosphotransferase, N-(2-AMINOETHYL)-5-CHLOROISOQUINOLINE-8-SULFONAMIDE, NICKEL (II) ION, ... (4 entities in total)
• Functional Keywords: ser/thr/tyr protein kinase, phosphotransferase, phosphorylation, cytosol, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Legionella pneumophila 130b
• Total number of polymer chains: 1
• Total formula weight: 39989.26

Authors

Berghuis, A.M.,Fong, D.H.,Xiong, B.,Hwang, J. (deposition date: 2010-12-20, release date: 2011-05-18, Last modification date: 2023-09-13)

Primary citation

Fong, D.H.,Xiong, B.,Hwang, J.,Berghuis, A.M.
Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.
Plos One, 6:e19589-e19589, 2011

PubMed Abstract: 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.

PubMed: 21573013
DOI: 10.1371/journal.pone.0019589

Experimental method

X-RAY DIFFRACTION (2.9 Å)