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| | ==CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH BMS-066 AKA 2-METHOXY-N-({6-[3-METHYL-7-(METHYLAMINO)-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0, 6]DODECA-1(9),2(6),4,7,11-PENTAEN-11-YL]PYRIDIN-2-YL}METHY L)ACETAMIDE== | | ==CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH BMS-066 AKA 2-METHOXY-N-({6-[3-METHYL-7-(METHYLAMINO)-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0, 6]DODECA-1(9),2(6),4,7,11-PENTAEN-11-YL]PYRIDIN-2-YL}METHY L)ACETAMIDE== |
| - | <StructureSection load='4wov' size='340' side='right' caption='[[4wov]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4wov' size='340' side='right'caption='[[4wov]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wov]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WOV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WOV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wov]] 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=4WOV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WOV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3SM:2-METHOXY-N-({6-[1-METHYL-4-(METHYLAMINO)-1,6-DIHYDROIMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-7-YL]PYRIDIN-2-YL}METHYL)ACETAMIDE'>3SM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3SM:2-METHOXY-N-({6-[1-METHYL-4-(METHYLAMINO)-1,6-DIHYDROIMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-7-YL]PYRIDIN-2-YL}METHYL)ACETAMIDE'>3SM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TYK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4wov FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wov OCA], [https://pdbe.org/4wov PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wov RCSB], [https://www.ebi.ac.uk/pdbsum/4wov PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wov ProSAT]</span></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>
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| - | <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=4wov FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wov OCA], [http://pdbe.org/4wov PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wov RCSB], [http://www.ebi.ac.uk/pdbsum/4wov PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wov ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == 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. | + | [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 == | | == 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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wov" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wov" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Muckelbauer, J K]] | + | [[Category: Muckelbauer JK]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Pseudokinase]]
| + | |
| - | [[Category: Transferase-inhibitor complex]]
| + | |
| - | [[Category: Tyk2]]
| + | |
| Structural highlights
Disease
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: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
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.[1]
Publication Abstract from PubMed
Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified which bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor (IFNAR), but not Tyk2-independent signaling and transcriptional cellular assays including stimulation through the receptors for IL-2 (JAK1 and JAK3 dependent) and thrombopoietin (JAK2 dependent) demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.
Tyrosine Kinase 2-Mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of its Pseudokinase Domain.,Tokarski JS, Zupa-Fernandez A, Tredup JA, Pike K, Chang C, Xie D, Cheng L, Pedicord D, Muckelbauer J, Johnson SR, Wu S, Edavettal SC, Hong Y, Witmer MR, Elkin LL, Blat Y, Pitts WJ, Weinstein DS, Burke JR J Biol Chem. 2015 Mar 11. pii: jbc.M114.619502. PMID:25762719[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
- ↑ Tokarski JS, Zupa-Fernandez A, Tredup JA, Pike K, Chang C, Xie D, Cheng L, Pedicord D, Muckelbauer J, Johnson SR, Wu S, Edavettal SC, Hong Y, Witmer MR, Elkin LL, Blat Y, Pitts WJ, Weinstein DS, Burke JR. Tyrosine Kinase 2-Mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of its Pseudokinase Domain. J Biol Chem. 2015 Mar 11. pii: jbc.M114.619502. PMID:25762719 doi:http://dx.doi.org/10.1074/jbc.M114.619502
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