PXD009724

PXD009724 is an original dataset announced via ProteomeXchange.

Title	Small-molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling
Description	RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2, and inhibition of RIPK2 by kinase inhibitors is an emerging strategy to ameliorate NOD-mediated pathologies. However, the role for RIPK2’s kinase activity remains unclear. 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 2 and 3 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-competitive RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivo NOD2 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:44:58.750.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jenny Ward
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2018-05-09 08:46:57	ID requested
1	2018-07-25 02:20:32	announced
⏵ 2	2024-10-22 04:44:59	announced	2024-10-22: Updated project metadata.

10.15252/embj.201899372;

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, Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling. EMBO J, 37(17):(2018) [pubmed]

curator keyword: Biological

submitter keyword: RIPK2, chemical proteomics,Ponatinib

Kilian Huber
contact affiliation	Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, UK Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, UK
contact email	kilian.huber@sgc.ox.ac.uk
lab head
Jenny Ward
contact affiliation	University of Oxford
contact email	jennifer.ward@ndm.ox.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2018/07/PXD009724

PRIDE project URI

• PRIDE
  1. PXD009724
     1. Label: PRIDE project
     2. Name: Small-molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling