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

Research output: Contribution to journalArticle

  • Matous Hrdinka
  • Lisa Schlicher
  • Bing Dai
  • Daniel M. Pinkas
  • Joshua C. Bufton
  • Sarah Picaud
  • Jennifer A. Ward
  • Catherine Rogers
  • Chalada Suebsuwong
  • Sameer Nikhar
  • Gregory D. Cuny
  • Kilian V.M. Huber
  • Panagis Filippakopoulos
  • Alex N. Bullock
  • Alexei Degterev
  • Mads Gyrd-Hansen
Original languageEnglish
Article numbere99372
Number of pages16
JournalEMBO Journal
Volume37
Issue number17
Early online date19 Jul 2018
DOIs
DateAccepted/In press - 22 Jun 2018
DateE-pub ahead of print - 19 Jul 2018
DatePublished (current) - 3 Sep 2018

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.

    Research areas

  • kinase inhibitor, NOD2 signaling, RIPK2, ubiquitin, XIAP

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via EMBO Press at http://emboj.embopress.org/content/37/17/e99372 . Please refer to any applicable terms of use of the publisher.

    Final published version, 4 MB, PDF-document

    Licence: CC BY

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