1. Academic Validation
  2. Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling

  • EMBO J. 2018 Sep 3;37(17):e99372. doi: 10.15252/embj.201899372.
Matous Hrdinka 1 Lisa Schlicher 1 Bing Dai 2 Daniel M Pinkas 3 Joshua C Bufton 3 Sarah Picaud 3 Jennifer A Ward 3 4 Catherine Rogers 3 4 Chalada Suebsuwong 5 Sameer Nikhar 6 Gregory D Cuny 6 Kilian Vm Huber 3 4 Panagis Filippakopoulos 3 Alex N Bullock 3 Alexei Degterev 7 Mads Gyrd-Hansen 8
Affiliations

Affiliations

  • 1 Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 2 Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA, USA.
  • 3 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.
  • 4 Nuffield Department of Clinical Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
  • 5 Department of Chemistry, University of Houston, Houston, TX, USA.
  • 6 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
  • 7 Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA, USA alexei.degterev@tufts.edu mads.gyrd-hansen@ludwig.ox.ac.uk.
  • 8 Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK alexei.degterev@tufts.edu mads.gyrd-hansen@ludwig.ox.ac.uk.
Abstract

RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling.

Keywords

XIAP; NOD2 signaling; RIPK2; kinase inhibitor; ubiquitin.

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