8i2n

From Proteopedia

(Difference between revisions)

Current revision

The RIPK1 kinase domain in complex with QY7-2B compound

Structural highlights

8i2n 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 2.29Å
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

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.,Qin Y, Li D, Qi C, Xiang H, Meng H, Liu J, Zhou S, Gong X, Li Y, Xu G, Zu R, Xie H, Xu Y, Xu G, Zhang Z, Chen S, Pan L, Li Y, Tan L Acta Pharm Sin B. 2024 Jan;14(1):319-334. doi: 10.1016/j.apsb.2023.10.021. Epub , 2023 Nov 8. PMID:38261830^[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
↑ Qin Y, Li D, Qi C, Xiang H, Meng H, Liu J, Zhou S, Gong X, Li Y, Xu G, Zu R, Xie H, Xu Y, Xu G, Zhang Z, Chen S, Pan L, Li Y, Tan L. Structure-based development of potent and selective type-II kinase inhibitors of RIPK1. Acta Pharm Sin B. 2024 Jan;14(1):319-334. PMID:38261830 doi:10.1016/j.apsb.2023.10.021

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8i2n"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8i2n is ON HOLD
+==The RIPK1 kinase domain in complex with QY7-2B compound==
+<StructureSection load='8i2n' size='340' side='right'caption='[[8i2n]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8i2n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8I2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8I2N FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8i2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8i2n OCA], [https://pdbe.org/8i2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8i2n RCSB], [https://www.ebi.ac.uk/pdbsum/8i2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8i2n ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/RIPK1_HUMAN 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.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
-Authors:
+Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.,Qin Y, Li D, Qi C, Xiang H, Meng H, Liu J, Zhou S, Gong X, Li Y, Xu G, Zu R, Xie H, Xu Y, Xu G, Zhang Z, Chen S, Pan L, Li Y, Tan L Acta Pharm Sin B. 2024 Jan;14(1):319-334. doi: 10.1016/j.apsb.2023.10.021. Epub , 2023 Nov 8. PMID:38261830<ref>PMID:38261830</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8i2n" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Gong XY]]
+[[Category: Li Y]]
+[[Category: Meng HY]]
+[[Category: Pan LF]]

8i2n

From Proteopedia

Current revision

The RIPK1 kinase domain in complex with QY7-2B compound

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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