Structure of IDP91189
Inhibition of an antibiotic resistance enzyme: crystal structure of aminoglycoside phosphotransferase APH(2")-ID/APH(2")-IVA in complex with kanamycin inhibited with quercetin
Edit deposit information
- CSGID target
- IDP91189
- PDB Id
- 4DFU (NCBI MMDB)
- Authors
- P.J.Stogios,G.Minasov,A.Dong,E.Evdokimova,E.Egorova,R.Di Leo,H.Li,T.Shakya,G.D.Wright,A.Savchenko,W.F.Anderson,Center For Structural Genomics Of Infectious Diseases (Csgid)
- Responsible person
- Peter Stogios
- Responsible lab
- University of Calgary
- Deposition Date
- Jan 24, 2012
- Release Date
- Feb 08, 2012
Annotation
- Description
- From the publication "A small molecule discrimination map of the antibiotic resistance kinome" Pubmed ID 22195561: 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.
- Functional assignment
- kinase
Ligands
| Ligand code | Name | Ligand type |
|---|---|---|
| QUE | 3,5,7,3',4'-pentahydroxyflavone | crystallization |
| KAN | biological | |
| MSE | modified residue | |
| 175 | 3,5-dihydro-5-methylidene-4h-imidazol-4-on |
Structure information
Unit cell parameters
- Space Group
- P 1 21 1
- Unit Cell
-
a=43.14Å, b=101.81Å, c=70.25Å
α=90.00, β=96.86, γ=90.00 - Solvent content
- Matthews coefficient
- Resolution range
- 19.84-1.98Å (2.05-1.98Å)
- Rall(%)
- 22.2
- Rwork(%)
- 21.9 (33.4)
- Rfree(%)
- 27.0 (34.4)
- Num. observed reflections
- 85487 (8090)
- Num. Rfree reflections
- 4060 (378)
- Completeness(%)
- 98.8 (97.0)
- Num Atoms
- 4816
- Num Waters
- 168
- Num Hetatoms
- 452
- Model mean isotropic B factor
- 68.890Å2
- RMSD bond length
- 0.008Å
- RMSD bond angle
- 1.247°
- RMSD dihedral angle
- 14.608°
- Filename uploaded
- 4DFU.pdb (uploaded on Feb 14, 2012 9:46 AM)
- Inserted
- Feb 14, 2012