4gj2
From Proteopedia
(Difference between revisions)
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| - | + | ==Tyk2 (JH1) in complex with 2,6-dichloro-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide== | |
| - | + | <StructureSection load='4gj2' size='340' side='right' caption='[[4gj2]], [[Resolution|resolution]] 2.40Å' scene=''> | |
| - | { | + | == Structural highlights == |
| - | + | <table><tr><td colspan='2'>[[4gj2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GJ2 FirstGlance]. <br> | |
| - | ==Disease== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0XH:2,6-DICHLORO-N-[2-({[(1R,2R)-2-FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4-YL]BENZAMIDE'>0XH</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gih|4gih]], [[4gii|4gii]], [[4gi3|4gi3]], [[4gvj|4gvj]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tyk2 gene ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gj2 RCSB], [http://www.ebi.ac.uk/pdbsum/4gj2 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
[[http://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:[http://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. | [[http://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:[http://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 == | ||
| + | [[http://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 == | ||
| + | Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-gamma (IFNgamma), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo. | ||
| - | + | Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors.,Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, Devoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29. PMID:23668484<ref>PMID:23668484</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | == | + | ==See Also== |
| - | + | *[[Tyrosine kinase|Tyrosine kinase]] | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific protein-tyrosine kinase]] | [[Category: Non-specific protein-tyrosine kinase]] | ||
| - | [[Category: Ultsch, M H | + | [[Category: Ultsch, M H]] |
[[Category: Atp binding]] | [[Category: Atp binding]] | ||
[[Category: Kinase]] | [[Category: Kinase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 11:01, 21 December 2014
Tyk2 (JH1) in complex with 2,6-dichloro-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide
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