Human Receptor-Interacting Serine/Threonine-Protein Kinase 2 (RIPK2); A Target Enabling Package
- Peter Canning1
- Daniel M. Pinkas1
- Joshua C. Bufton1
- Sarah Picaud1
- Jennifer A. Ward1
- Catherine Rogers1
- Benedict-Tilman Berger2
- Matous Hrdinka3
- Qui Ruan4
- Chalada Suebsuwong5
- Lisa Schlicher3
- Bing Dai4
- Jenny L. Maki4
- Soumya S. Ray6
- Danish Saleh7
- Sameer Nikhar8
- Tobias Schwerd9
- Holm H. Uhlig9
- Stefan Knapp2
- Susanne Muller-Knapp2
- Paul E. Brennan1
- Kilian V. M. Huber1
- Panagis Filippakopoulos1
- Gregory D. Cuny8
- Alexei Degterev4
- Mads Gyrd-Hansen3
- Alex N. Bullock1
- 1. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, UK
- 2. Structural Genomics Consortium, Goethe University Frankfurt, Germany
- 3. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford
- 4. Department of Developmental, Molecular, & Chemical Biology, Tufts University School of Medicine
- 5. Department of Chemistry, Science and Research Building 2, University of Houston
- 6. Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School
- 7. Medical Scientist Training Program and Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine
- 8. Department of Pharmacology and Pharmaceutical Sciences, Science and Research Building 2, University of Houston
- 9. Translational Gastroenterology Unit, Nuffield Department of Medicine and Department of Pediatrics, John Radcliffe Hospital, University of Oxford
Description
RIPK2 inflammatory signalling downstream from the bacteria-sensing receptors NOD1 and NOD2 is associated with auto-immune and inflammatory conditions. RIPK2 inhibition has shown promise in disease models of inflammatory bowel disease and multiple sclerosis. In this TEP, we reveal a lack of correlation between inhibitor efficacy in cells and their potency using in vitro kinase assays. We show that RIPK2 kinase activity is in fact dispensable for NOD2 inflammatory signalling and that RIPK2 inhibitors function instead by antagonizing XIAP-binding and ubiquitination of RIPK2. We characterise the molecular basis for this effect. We also solved the first crystal structure of the RIPK2 kinase domain and applied a range of biochemical and cellular assays to profile type I and type II RIPK2 kinase inhibitors. Overall, our study illustrates how to target the ATP-binding pocket in RIPK2 to interfere with the RIPK2-XIAP interaction for modulation of NOD signalling.
Notes
Files
RIPK2_TEP.pdf
Additional details
Related works
- Is part of
- https://www.thesgc.org/tep (URL)
Funding
- Wellcome Trust
- A UK Hub to Catalyse Open Target Discovery. 106169