2bkk | pdb_00002bkk
CRYSTAL STRUCTURE OF AMINOGLYCOSIDE PHOSPHOTRANSFERASE APH (3')-IIIA IN COMPLEX WITH THE INHIBITOR AR_3A
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| 2bkk, resolution 2.15Å | |||||||||||||
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| Sites: | AC1 | ||||||||||||
| Ligands: | ADP, MG | ||||||||||||
| Activity: | Kanamycin kinase, with EC number 2.7.1.95 | ||||||||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
Overview
Aminoglycoside phosphotransferase (3')-IIIa (APH) is a bacterial kinase that confers antibiotic resistance to many pathogenic bacteria and shares structural homology with eukaryotic protein kinases. We report here the crystal structure of APH, trapped in an inactive conformation by a tailor-made inhibitory ankyrin repeat (AR) protein, at 2.15 A resolution. The inhibitor was selected from a combinatorial library of designed AR proteins. The AR protein binds the C-terminal lobe of APH and thereby stabilizes three alpha helices, which are necessary for substrate binding, in a significantly displaced conformation. BIAcore analysis and kinetic enzyme inhibition experiments are consistent with the proposed allosteric inhibition mechanism. In contrast to most small-molecule kinase inhibitors, the AR proteins are not restricted to active site binding, allowing for higher specificity. Inactive conformations of pharmaceutically relevant enzymes, as can be elucidated with the approach presented here, represent powerful starting points for rational drug design.
About this Structure
2BKK is a Protein complex structure of sequences from Enterococcus faecalis. Full crystallographic information is available from OCA.
Reference
Allosteric inhibition of aminoglycoside phosphotransferase by a designed ankyrin repeat protein., Kohl A, Amstutz P, Parizek P, Binz HK, Briand C, Capitani G, Forrer P, Pluckthun A, Grutter MG, Structure. 2005 Aug;13(8):1131-41. PMID:16084385
Page seeded by OCA on Mon Mar 31 02:07:47 2008
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- Enterococcus faecalis
- Kanamycin kinase
- Protein complex
- Amstutz, P.
- Binz, H K.
- Briand, C.
- Capitani, G.
- Forrer, P.
- Grutter, M G.
- Kohl, A.
- Parizek, P.
- Pluckthun, A.
- Ankyrin repeat
- Antibiotic resistance
- Atp-binding
- Co-crystallization
- Designed repeat protein
- Drug design
- Enzyme inhibition
- Inhibitor design
- Kinase
- Kinase inhibition
- Plasmid
- Transferase
