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

DOI: 10.15252/embj.201899372

Authors: Matous Hrdinka (Ludwig Institute for Cancer Research, University of Oxford) , Lisa Schlicher (Ludwig Institute for Cancer Research, University of Oxford) , Bing Dai (Tufts University School of Medicine) , Daniel M. Pinkas (Structural Genomics Consortium, University of Oxford) , Joshua C. Bufton (Structural Genomics Consortium, University of Oxford) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Jennifer A. Ward (Structural Genomics Consortium, University of Oxford) , Catherine Rogers (Structural Genomics Consortium, University of Oxford) , Chalada Suebsuwong (University of Houston) , Sameer Nikhar (Structural Genomics Consortium, University of Oxford) , Gregory D. Cuny (University of Houston) , Kilian V. M. Huber (Structural Genomics Consortium, University of Oxford; Target Discovery Institute) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Alexei Degterev (University School of Medicine, Boston) , Mads Gyrd‐hansen (Ludwig Institute for Cancer Research, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal

State: Published (Approved)
Published: July 2018
Diamond Proposal Number(s): 15433

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.

Journal Keywords: kinase inhibitor; NOD2 signaling; RIPK2; ubiquitin; XIAP

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 25/07/2018 09:52

Documents:
embj.201899372.full.pdf

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)