7fd0

Crystal Structure of human RIPK1 kinase domain in complex with a novel inhibitorCrystal Structure of human RIPK1 kinase domain in complex with a novel inhibitor

Structural highlights

7fd0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RIPK1_HUMAN Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.

Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis.,Yang X, Lu H, Xie H, Zhang B, Nie T, Fan C, Yang T, Xu Y, Su H, Tang W, Zhou B Angew Chem Int Ed Engl. 2022 Jan 26;61(5):e202114922. doi:, 10.1002/anie.202114922. Epub 2021 Dec 16. PMID:34851543^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000 Dec;1(6):489-95. PMID:11101870 doi:10.1038/82732
↑ Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12;137(6):1112-23. doi: 10.1016/j.cell.2009.05.037. PMID:19524513 doi:10.1016/j.cell.2009.05.037
↑ He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009 Jun 12;137(6):1100-11. doi: 10.1016/j.cell.2009.05.021. PMID:19524512 doi:10.1016/j.cell.2009.05.021
↑ Yang X, Lu H, Xie H, Zhang B, Nie T, Fan C, Yang T, Xu Y, Su H, Tang W, Zhou B. Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis. Angew Chem Int Ed Engl. 2022 Jan 26;61(5):e202114922. doi:, 10.1002/anie.202114922. Epub 2021 Dec 16. PMID:34851543 doi:http://dx.doi.org/10.1002/anie.202114922

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OCA

[1] Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000 Dec;1(6):489-95. PMID:11101870 doi:10.1038/82732

[2] Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12;137(6):1112-23. doi: 10.1016/j.cell.2009.05.037. PMID:19524513 doi:10.1016/j.cell.2009.05.037

[3] He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009 Jun 12;137(6):1100-11. doi: 10.1016/j.cell.2009.05.021. PMID:19524512 doi:10.1016/j.cell.2009.05.021

[4] Yang X, Lu H, Xie H, Zhang B, Nie T, Fan C, Yang T, Xu Y, Su H, Tang W, Zhou B. Potent and Selective RIPK1 Inhibitors Targeting Dual-Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis. Angew Chem Int Ed Engl. 2022 Jan 26;61(5):e202114922. doi:, 10.1002/anie.202114922. Epub 2021 Dec 16. PMID:34851543 doi:http://dx.doi.org/10.1002/anie.202114922

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