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9hy9
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of an allosteric inhibitor bound to human RIPK1 kinase domain== | |
| + | <StructureSection load='9hy9' size='340' side='right'caption='[[9hy9]], [[Resolution|resolution]] 2.29Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9hy9]] 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=9HY9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HY9 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]] 2.29Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IX9:~{N}-[(1~{S})-1-(2-chloranyl-6-fluoranyl-phenyl)ethyl]-4-fluoranyl-1-[2-fluoranyl-5-(1-methylpyrazol-4-yl)phenyl]carbonyl-piperidine-4-carboxamide'>A1IX9</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></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=9hy9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hy9 OCA], [https://pdbe.org/9hy9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hy9 RCSB], [https://www.ebi.ac.uk/pdbsum/9hy9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hy9 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) is a critical signalling protein that regulates inflammation and cell death in response to TNF signalling. Inhibiting RIPK1 kinase activity prevents neuronal cell death in various animal models, making it a promising therapeutic target for neurodegenerative, inflammatory, and autoimmune disorders. To identify novel allosteric RIPK1 inhibitors, we used a parallel virtual screening strategy that employed structure-based pharmacophore, shape-based, and fuzzy pharmacophore similarity approaches. Structure-guided optimization enabled by X-ray crystallography led to the discovery of a potent and selective piperidinecarboxamide inhibitor with an acceptable pharmacokinetic (PK) profile and limited brain exposure. This work highlights the effectiveness of virtual screening, followed by structure-guided optimization, in identifying progressible allosteric kinase inhibitors. | ||
| - | + | Allosteric targeting of RIPK1: discovery of novel inhibitors via parallel virtual screening and structure-guided optimization.,Vijayan RSK, Hamilton MM, Pfaffinger DE, Alvarez FG, Reyna NJ, Bardenhagen JP, Shepard H, Rodriguez C, Goodwani S, Lightfoot Y, Maskos K, Johannsson S, Kempf G, Xu QA, Neumann L, Jiang Y, Do MG, Jones P, Lewis RT, Ray WJ, Cross JB RSC Med Chem. 2025 Sep 17. doi: 10.1039/d5md00317b. PMID:40969564<ref>PMID:40969564</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9hy9" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Cross JB]] | ||
| + | [[Category: Johannsson S]] | ||
| + | [[Category: Kempf G]] | ||
| + | [[Category: Maskos K]] | ||
| + | [[Category: Neumann L]] | ||
Current revision
Crystal structure of an allosteric inhibitor bound to human RIPK1 kinase domain
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