ArticlePloS one2017
Structures of the inactive and active states of RIP2 kinase inform on the mechanism of activation.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Article
- Delineation of signaling routes that underlie differences in macrophage phenotypic states.NAR molecular medicine · 2025Article
- Current advances on RIPK2 and its inhibitors in pathological processes: a comprehensive review.Frontiers in molecular neuroscience · 2025Review
- Article
- Article
- Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface.Life science alliance · 2023Article
- Roles of RIPK1 as a stress sentinel coordinating cell survival and immunogenic cell death.Nature reviews. Molecular cell biology · 2023Review
- Article
- Recent advances in the development of RIPK2 modulators for the treatment of inflammatory diseases.Frontiers in pharmacology · 2023Review
- scDual-Seq ofFrontiers in immunology · 2023Article
- Foot-and-Mouth Disease Virus: Molecular Interplays with IFN Response and the Importance of the Model.Viruses · 2022Review
- Integrating Network Pharmacology and Experimental Validation to Explore the Key Mechanism of Gubitong Recipe in the Treatment of Osteoarthritis.Computational and mathematical methods in medicine · 2022Article
- Assaying RIPK2 Activation by Complex Formation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- ProtCID: a data resource for structural information on protein interactions.Nature communications · 2020Article
- XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures.Life science alliance · 2019Article
- Review
- Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation.Nature communications · 2019Article
- NOD Signaling and Cell Death.Frontiers in cell and developmental biology · 2019Review
- RIP2 filament formation is required for NOD2 dependent NF-κB signalling.Nature communications · 2018Article
- Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.The EMBO journal · 2018Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Innate immune receptors NOD1 and NOD2 are activated by bacterial peptidoglycans leading to recruitment of adaptor kinase RIP2, which, upon phosphorylation and ubiquitination, becomes a scaffold for downstream effectors. The kinase domain (RIP2K) is a pharmaceutical target for inflammatory diseases caused by aberrant NOD2-RIP2 signalling. Although structures of active RIP2K in complex with inhibitors have been reported, the mechanism of RIP2K activation remains to be elucidated. Here we analyse RIP2K activation by combining crystal structures of the active and inactive states with mass spectrometric characterization of their phosphorylation profiles. The active state has Helix αC inwardly displaced and the phosphorylated Activation Segment (AS) disordered, whilst in the inactive state Helix αC is outwardly displaced and packed against the helical, non-phosphorylated AS. Biophysical measurements show that the active state is a stable dimer whilst the inactive kinase is in a monomer-dimer equilibrium, consistent with the observed structural differences at the dimer interface. We conclude that RIP2 kinase auto-phosphorylation is intimately coupled to dimerization, similar to the case of BRAF. Our results will help drug design efforts targeting RIP2 as a potential treatment for NOD2-RIP2 related inflammatory diseases.
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