4DFU

Inhibition of an antibiotic resistance enzyme: crystal structure of aminoglycoside phosphotransferase APH(2")-ID/APH(2")-IVA in complex with kanamycin inhibited with quercetin

Replaces:  3VCQReplaces:  3R82

Summary for 4DFU

• Entry DOI: 10.2210/pdb4dfu/pdb
• Related: 4DBX 4DE4 4DFB
• Descriptor: APH(2")-Id, KANAMYCIN A, 3,5,7,3',4'-PENTAHYDROXYFLAVONE, ... (5 entities in total)
• Functional Keywords: structural genomics, center for structural genomics of infectious diseases, csgid, eukaryotic protein kinase-like fold, transferase-antibiotic-inhibitor complex, aminoglycoside phosphotransferase, kinase, transferase, aminoglycosides, kanamycin, flavanoids, quercetin, intracellular, antibotic, transferase-antibotic-inhibitor complex, transferase/antibotic/inhibitor
• Biological source: Enterococcus casseliflavus
• Total number of polymer chains: 2
• Total formula weight: 78504.69

Authors

Stogios, P.J.,Minasov, G.,Dong, A.,Evdokimova, E.,Egorova, E.,Di Leo, R.,Li, H.,Shakya, T.,Wright, G.D.,Savchenko, A.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2012-01-24, release date: 2012-02-08, Last modification date: 2024-11-20)

Primary citation

Shakya, T.,Stogios, P.J.,Waglechner, N.,Evdokimova, E.,Ejim, L.,Blanchard, J.E.,McArthur, A.G.,Savchenko, A.,Wright, G.D.
A small molecule discrimination map of the antibiotic resistance kinome.
Chem.Biol., 18:1591-1601, 2011

PubMed Abstract: Kinase-mediated resistance to antibiotics is a significant clinical challenge. These enzymes share a common protein fold characteristic of Ser/Thr/Tyr protein kinases. We screened 14 antibiotic resistance kinases against 80 chemically diverse protein kinase inhibitors to map resistance kinase chemical space. The screens identified molecules with both broad and narrow inhibition profiles, proving that protein kinase inhibitors offer privileged chemical matter with the potential to block antibiotic resistance. One example is the flavonol quercetin, which inhibited a number of resistance kinases in vitro and in vivo. This activity was rationalized by determination of the crystal structure of the aminoglycoside kinase APH(2″)-IVa in complex with quercetin and its antibiotic substrate kanamycin. Our data demonstrate that protein kinase inhibitors offer chemical scaffolds that can block antibiotic resistance, providing leads for co-drug design.

PubMed: 22195561
DOI: 10.1016/j.chembiol.2011.10.018

Experimental method

X-RAY DIFFRACTION (1.98 Å)