2bkk

From Proteopedia

Revision as of 15:36, 5 November 2007

CRYSTAL STRUCTURE OF AMINOGLYCOSIDE PHOSPHOTRANSFERASE APH (3')-IIIA IN COMPLEX WITH THE INHIBITOR AR_3A

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 with MG and ADP as ligands. Active as Kanamycin kinase, with EC number 2.7.1.95 Structure known Active Site: AC1. 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 Nov 5 17:41:31 2007