View source for 7uyu


==Crystal structure of TYK2 kinase domain in complex with compound 30==
<StructureSection load='7uyu' size='340' side='right'caption='[[7uyu]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7uyu]] 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=7UYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UYU 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]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OV0:2-[2,6-bis(fluoranyl)phenyl]-4-[(4-pyrrolidin-1-ylcarbonylphenyl)amino]pyrrolo[3,4-b]pyridin-5-one'>OV0</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7uyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uyu OCA], [https://pdbe.org/7uyu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uyu RCSB], [https://www.ebi.ac.uk/pdbsum/7uyu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uyu ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:[https://omim.org/entry/611521 611521]; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.
== Function ==
[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases. Herein, we report the discovery of a series of highly selective catalytic site TYK2 inhibitors designed using FEP+ and structurally enabled design starting from a virtual screen hit. We highlight the structure-based optimization to identify a lead candidate 30, a potent cellular TYK2 inhibitor with excellent selectivity, pharmacokinetic properties, and in vivo efficacy in a mouse psoriasis model.

Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.,Leit S, Greenwood JR, Mondal S, Carriero S, Dahlgren M, Harriman GC, Kennedy-Smith JJ, Kapeller R, Lawson JP, Romero DL, Toms AV, Shelley M, Wester RT, Westlin W, McElwee JJ, Miao W, Edmondson SD, Masse CE Bioorg Med Chem Lett. 2022 Oct 1;73:128891. doi: 10.1016/j.bmcl.2022.128891. Epub , 2022 Jul 13. PMID:35842205<ref>PMID:35842205</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7uyu" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Carriero S]]
[[Category: Dahlgren M]]
[[Category: Edmondson SD]]
[[Category: Greenwood JR]]
[[Category: Harriman GC]]
[[Category: Kapeller R]]
[[Category: Kennedy-Smith JJ]]
[[Category: Lawson JP]]
[[Category: Leit S]]
[[Category: Massee CE]]
[[Category: Mc Elwee JJ]]
[[Category: Miao W]]
[[Category: Mondal S]]
[[Category: Romero DL]]
[[Category: Shelley M]]
[[Category: Toms AV]]
[[Category: Wester RT]]
[[Category: Westlin W]]