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Detection of Ligand-induced Conformational Changes in the Activation Loop of Aurora-A Kinase by PELDOR Spectroscopy.

Burgess, SG, Grazia Concilio, M, Bayliss, R and Fielding, AJ (2016) Detection of Ligand-induced Conformational Changes in the Activation Loop of Aurora-A Kinase by PELDOR Spectroscopy. ChemistryOpen, 5 (6). pp. 531-534. ISSN 2191-1363

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Abstract

The structure of protein kinases has been extensively studied by protein crystallography. Conformational movement of the kinase activation loop is thought to be crucial for regulation of activity; however, in many cases the position of the activation loop in solution is unknown. Protein kinases are an important class of therapeutic target and kinase inhibitors are classified by their effect on the activation loop. Here, we report the use of pulsed electron double resonance (PELDOR) and site-directed spin labeling to monitor conformational changes through the insertion of MTSL [S-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1 H-pyrrol-3-yl)methyl methanesulfonothioate] on the dynamic activation loop and a stable site on the outer surface of the enzyme. The action of different ligands such as microtubule-associated protein (TPX2) and inhibitors could be discriminated as well as their ability to lock the activation loop in a fixed conformation. This study provides evidence for structural adaptations that could be used for drug design and a methodological approach that has potential to characterize inhibitors in development.

Item Type: Article
Uncontrolled Keywords: PELDOR spectroscopy; drug design; electron paramagnetic resonance; inhibitor; protein kinases
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Wiley Open Access
Related URLs:
Date Deposited: 04 Oct 2018 10:03
Last Modified: 04 Oct 2018 12:18
DOI or Identification number: 10.1002/open.201600101
URI: http://researchonline.ljmu.ac.uk/id/eprint/9414

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