In order to achieve greater selectivity in drug discovery, researchers in both academia and industry are targeting cell regulatory systems. This often involves targeting the protein–protein interactions of regulatory multiprotein assemblies. Protein–protein interfaces are widely recognized to be challenging targets as they tend to be large and relatively flat, and therefore usually do not have the concave binding sites that characterize the so-called ‘druggable genome’. One such prototypic multiprotein target is the Notch transcription complex, where an extensive network of protein–protein interactions stabilize the ternary complex comprising the ankyrin domain, CSL (CBF1/suppressor of Hairless/Lag-1) and MAML (Mastermind-like). Enhanced Notch activity is implicated in the development of T-ALL (T-cell acute lymphoblastic leukaemia) and selective inhibitors of Notch would be useful cancer medicines. In the present paper, we describe a fragment-based approach to explore the druggability of the ankyrin domain. Using biophysical methods and X-ray crystal structure analyses, we demonstrate that molecules can bind to the surface of the ankyrin domain at the interface region with CSL and MAML. We show that they probably represent starting points for designing larger compounds that can inhibit important protein–protein interactions that stabilize the Notch complex. Given the relatively featureless topography of the ankyrin domain, this unexpected development should encourage others to explore the druggability of such challenging multiprotein systems using fragment-based approaches.
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Conference Article|
September 21 2011
Probing the druggability of protein–protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach
Noha Abdel-Rahman;
Noha Abdel-Rahman
1
*Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
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Alfonso Martinez-Arias;
Alfonso Martinez-Arias
†Department of Genetics, University of Cambridge, Cambridge CB2 3EH, U.K.
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Tom L. Blundell
Tom L. Blundell
2
*Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, U.K.
2To whom correspondence should be addressed (email tlb20@cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 27 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem Soc Trans (2011) 39 (5): 1327–1333.
Article history
Received:
May 27 2011
Citation
Noha Abdel-Rahman, Alfonso Martinez-Arias, Tom L. Blundell; Probing the druggability of protein–protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach. Biochem Soc Trans 1 October 2011; 39 (5): 1327–1333. doi: https://doi.org/10.1042/BST0391327
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