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

Research output: Contribution to journal › Journal article › Research › peer-review

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Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. / Hrdinka, Matous; Schlicher, Lisa; Dai, Bing; Pinkas, Daniel M; Bufton, Joshua C; Picaud, Sarah; Ward, Jennifer A; Rogers, Catherine; Suebsuwong, Chalada; Nikhar, Sameer; Cuny, Gregory D; Huber, Kilian Vm; Filippakopoulos, Panagis; Bullock, Alex N; Degterev, Alexei; Gyrd-Hansen, Mads.

In: The EMBO Journal, Vol. 37, No. 17, 03.09.2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Hrdinka, M, Schlicher, L, Dai, B, Pinkas, DM, Bufton, JC, Picaud, S, Ward, JA, Rogers, C, Suebsuwong, C, Nikhar, S, Cuny, GD, Huber, KV, Filippakopoulos, P, Bullock, AN, Degterev, A & Gyrd-Hansen, M 2018, 'Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling', The EMBO Journal, vol. 37, no. 17. https://doi.org/10.15252/embj.201899372

APA

Hrdinka, M., Schlicher, L., Dai, B., Pinkas, D. M., Bufton, J. C., Picaud, S., Ward, J. A., Rogers, C., Suebsuwong, C., Nikhar, S., Cuny, G. D., Huber, K. V., Filippakopoulos, P., Bullock, A. N., Degterev, A., & Gyrd-Hansen, M. (2018). Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. The EMBO Journal, 37(17). https://doi.org/10.15252/embj.201899372

Vancouver

Hrdinka M, Schlicher L, Dai B, Pinkas DM, Bufton JC, Picaud S et al. Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. The EMBO Journal. 2018 Sep 3;37(17). https://doi.org/10.15252/embj.201899372

Author

Hrdinka, Matous ; Schlicher, Lisa ; Dai, Bing ; Pinkas, Daniel M ; Bufton, Joshua C ; Picaud, Sarah ; Ward, Jennifer A ; Rogers, Catherine ; Suebsuwong, Chalada ; Nikhar, Sameer ; Cuny, Gregory D ; Huber, Kilian Vm ; Filippakopoulos, Panagis ; Bullock, Alex N ; Degterev, Alexei ; Gyrd-Hansen, Mads. / Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. In: The EMBO Journal. 2018 ; Vol. 37, No. 17.

Bibtex

@article{689a7b4bc7d74ef2be92299065ecfe96,
title = "Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling",
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 = "Animals, Cell Line, Tumor, Female, Humans, Inhibitor of Apoptosis Proteins/genetics, Mice, Nod2 Signaling Adaptor Protein/genetics, Protein Kinase Inhibitors/pharmacology, Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors, Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors, Signal Transduction/drug effects, X-Linked Inhibitor of Apoptosis Protein/genetics",
author = "Matous Hrdinka and Lisa Schlicher and Bing Dai and Pinkas, {Daniel M} and Bufton, {Joshua C} and Sarah Picaud and Ward, {Jennifer A} and Catherine Rogers and Chalada Suebsuwong and Sameer Nikhar and Cuny, {Gregory D} and Huber, {Kilian Vm} and Panagis Filippakopoulos and Bullock, {Alex N} and Alexei Degterev and Mads Gyrd-Hansen",
note = "{\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2018",
month = sep,
day = "3",
doi = "10.15252/embj.201899372",
language = "English",
volume = "37",
journal = "E M B O Journal",
issn = "0261-4189",
publisher = "Wiley-Blackwell",
number = "17",

}

RIS

TY - JOUR

T1 - Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling

AU - Hrdinka, Matous

AU - Schlicher, Lisa

AU - Dai, Bing

AU - Pinkas, Daniel M

AU - Bufton, Joshua C

AU - Picaud, Sarah

AU - Ward, Jennifer A

AU - Rogers, Catherine

AU - Suebsuwong, Chalada

AU - Nikhar, Sameer

AU - Cuny, Gregory D

AU - Huber, Kilian Vm

AU - Filippakopoulos, Panagis

AU - Bullock, Alex N

AU - Degterev, Alexei

AU - Gyrd-Hansen, Mads

N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2018/9/3

Y1 - 2018/9/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line, Tumor

KW - Female

KW - Humans

KW - Inhibitor of Apoptosis Proteins/genetics

KW - Mice

KW - Nod2 Signaling Adaptor Protein/genetics

KW - Protein Kinase Inhibitors/pharmacology

KW - Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors

KW - Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors

KW - Signal Transduction/drug effects

KW - X-Linked Inhibitor of Apoptosis Protein/genetics

U2 - 10.15252/embj.201899372

DO - 10.15252/embj.201899372

M3 - Journal article

C2 - 30026309

VL - 37

JO - E M B O Journal

JF - E M B O Journal

SN - 0261-4189

IS - 17

ER -

ID: 280716915