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Issue 4, 2013
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Fingerprinting differential active site constraints of ATPases

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Abstract

The free energy provided by adenosine triphosphate (ATP) hydrolysis is central to many cellular processes and, therefore, the number of enzymes utilizing ATP as a substrate is almost innumerable. Modified analogues of ATP are a valuable means to understand the biological function of ATPases. Although these enzymes have evolved towards binding to ATP, large differences in active site architectures were found. In order to systematically access the specific active site constraints of different ATPases suitable tools are required. Here, we present the synthesis of six new ATP-based ATPase probes modified at three different positions of the nucleobase and the ribose, respectively. Subsequently, we studied the ATPases focal adhesion kinase FAK, the ubiquitin-activating protein UBA1 and the kinesin Eg5 as examples for ATPases that process ATP by different mechanisms. We find that for each of these enzymes at least one position in ATP can be modified without loss of acceptance by the enzyme. However, the positions at which modifications are tolerated significantly differ between the studied enzymes allowing fingerprints to be drawn for reactivity. The introduced ATP analogues may form the basis for the design of tailored probes with increased affinity and specificity for a specific ATPase of interest.

Graphical abstract: Fingerprinting differential active site constraints of ATPases

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Supplementary files

Article information


Submitted
05 Nov 2012
Accepted
10 Jan 2013
First published
15 Jan 2013

Chem. Sci., 2013,4, 1588-1596
Article type
Edge Article

Fingerprinting differential active site constraints of ATPases

S. M. Hacker, N. Hardt, A. Buntru, D. Pagliarini, M. Möckel, T. U. Mayer, M. Scheffner, C. R. Hauck and A. Marx, Chem. Sci., 2013, 4, 1588
DOI: 10.1039/C3SC21916J

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