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EMBO J. 2018 Sep 3;37(17). pii: e99372. doi: 10.15252/embj.201899372. Epub 2018 Jul 19.

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

Author information

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

PMID:
30026309
PMCID:
PMC6120666
DOI:
10.15252/embj.201899372
[Indexed for MEDLINE]
Free PMC Article

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