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Issue 3, 2011
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From cosubstrate similarity to inhibitor diversity—inhibitors of ADP-ribosyltransferases from kinase inhibitor screening

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Abstract

ADP-ribosyltransferases (ADP-RTs) use NAD+ to transfer an ADP-ribosyl group to target proteins. Although some ADP-RTs are bacterial toxins only few inhibitors are known. Here we present the development of fluorescence-based assays and a focussed library screening using kinase inhibitors as a new approach towards inhibitors of ADP-RTs. Different screening setups were established using surrogate small molecule substrates or the quantitation of the cofactor NAD+. Proof-of-principle screening experiments were performed using a kinase inhibitor library in order to target the NAD+ binding pockets. This led to the discovery of structurally different lead inhibitors for the mono-ADP-ribosyltransferases Mosquitocidal toxin (MTX) from Bacillus sphaericus SSII-1, C3bot toxin from Clostridium botulinum and CDTa from Clostridium difficile. The interaction of the inhibitors with the toxin proteins was analyzed by means of docking and binding free energy calculations. Binding at the nicotinamide subpocket, which shows a significant difference in the three enzymes, is used to explain the selectivity of the identified inhibitors and offers an opportunity for further development of potent and selective inhibitors.

Graphical abstract: From cosubstrate similarity to inhibitor diversity—inhibitors of ADP-ribosyltransferases from kinase inhibitor screening

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Publication details

The article was received on 11 Aug 2010, accepted on 10 Nov 2010 and first published on 06 Dec 2010


Article type: Paper
DOI: 10.1039/C0MB00151A
Citation: Mol. BioSyst., 2011,7, 799-808
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    From cosubstrate similarity to inhibitor diversity—inhibitors of ADP-ribosyltransferases from kinase inhibitor screening

    B. Maurer, U. Mathias, P. Papatheodorou, S. Shekfeh, J. Orth, T. Jank, C. Schwan, W. Sippl, K. Aktories and M. Jung, Mol. BioSyst., 2011, 7, 799
    DOI: 10.1039/C0MB00151A

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