8s85
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of JAK1 JH1 domain in complex with an inhibitor== | |
| + | <StructureSection load='8s85' size='340' side='right'caption='[[8s85]], [[Resolution|resolution]] 1.75Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8s85]] 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=8S85 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8S85 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]] 1.75Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1H5R:~{N}-(2-ethylphenyl)-~{N},1-dimethyl-imidazo[4,5-c]pyridin-6-amine'>A1H5R</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=8s85 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8s85 OCA], [https://pdbe.org/8s85 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8s85 RCSB], [https://www.ebi.ac.uk/pdbsum/8s85 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8s85 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T(H)1 and T(H)17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model. | ||
| - | + | Design of a potent and selective dual JAK1/TYK2 inhibitor.,Mammoliti O, Menet C, Cottereaux C, Blanc J, De Blieck A, Coti G, Geney R, Oste L, Ostyn K, Palisse A, Quinton E, Schmitt B, Borgonovi M, Parent I, Jagerschmidt C, De Vos S, Vayssiere B, Lopez-Ramos M, Shoji K, Brys R, Amantini D, Galien R, Joannesse C Bioorg Med Chem. 2024 Nov 15;114:117932. doi: 10.1016/j.bmc.2024.117932. Epub , 2024 Sep 30. PMID:39447537<ref>PMID:39447537</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8s85" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Flower TF]] | ||
| + | [[Category: Geney R]] | ||
| + | [[Category: Jestel A]] | ||
| + | [[Category: Lopez-Ramos M]] | ||
Current revision
Crystal structure of JAK1 JH1 domain in complex with an inhibitor
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