6n7d: Difference between revisions
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<StructureSection load='6n7d' size='340' side='right'caption='[[6n7d]], [[Resolution|resolution]] 1.78Å' scene=''> | <StructureSection load='6n7d' size='340' side='right'caption='[[6n7d]], [[Resolution|resolution]] 1.78Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6n7d]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6n7d]] is a 1 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=6N7D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N7D FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KF4:N-[5-(6-methoxy- | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.78Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KF4:~{N}-[5-(6-methoxy-1~{H}-indazol-5-yl)-1~{H}-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide'>KF4</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=6n7d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n7d OCA], [https://pdbe.org/6n7d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n7d RCSB], [https://www.ebi.ac.uk/pdbsum/6n7d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n7d ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6n7d" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6n7d" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Janus kinase 3D structures|Janus kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Brown D]] | |||
[[Category: Brown | [[Category: Lupardus PJ]] | ||
[[Category: Lupardus | |||
Latest revision as of 13:14, 23 October 2024
Structure of the human JAK1 kinase domain with compound 54Structure of the human JAK1 kinase domain with compound 54
Structural highlights
FunctionJAK1_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. Publication Abstract from PubMedDisruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively). Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.,Zak M, Hanan EJ, Lupardus P, Brown DG, Robinson C, Siu M, Lyssikatos JP, Romero FA, Zhao G, Kellar T, Mendonca R, Ray NC, Goodacre SC, Crackett PH, McLean N, Hurley CA, Yuen PW, Cheng YX, Liu X, Liimatta M, Kohli PB, Nonomiya J, Salmon G, Buckley G, Lloyd J, Gibbons P, Ghilardi N, Kenny JR, Johnson A Bioorg Med Chem Lett. 2019 Apr 4. pii: S0960-894X(19)30217-3. doi:, 10.1016/j.bmcl.2019.04.008. PMID:30981576[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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