7c3n

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==Crystal structure of JAK3 in complex with Delgocitinib==
==Crystal structure of JAK3 in complex with Delgocitinib==
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<StructureSection load='7c3n' size='340' side='right'caption='[[7c3n]]' scene=''>
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<StructureSection load='7c3n' size='340' side='right'caption='[[7c3n]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C3N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C3N FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7c3n]] is a 1 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=7C3N OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C3N FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7c3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c3n OCA], [http://pdbe.org/7c3n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c3n RCSB], [http://www.ebi.ac.uk/pdbsum/7c3n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c3n ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FHX:3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.4]octan-1-yl]-3-oxidanylidene-propanenitrile'>FHX</scene></td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">JAK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<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://proteopedia.org/fgij/fg.htm?mol=7c3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c3n OCA], [http://pdbe.org/7c3n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c3n RCSB], [http://www.ebi.ac.uk/pdbsum/7c3n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c3n ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:[http://omim.org/entry/600802 600802]]. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.<ref>PMID:15121872</ref> <ref>PMID:18250158</ref> <ref>PMID:15831699</ref> [:]<ref>PMID:7659163</ref> <ref>PMID:9354668</ref> <ref>PMID:9753072</ref> <ref>PMID:10982185</ref> <ref>PMID:14615376</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/JAK3_HUMAN JAK3_HUMAN]] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.<ref>PMID:8022485</ref> <ref>PMID:7662955</ref> <ref>PMID:20440074</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes, and are complex and multi-factorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and anti-dermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials, and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.
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Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders.,Noji S, Hara Y, Miura T, Yamanaka H, Maeda K, Hori A, Yamamoto H, Obika S, Inoue M, Hase Y, Orita T, Doi S, Adachi T, Tanimoto A, Oki C, Kimoto Y, Ogawa Y, Negoro T, Hashimoto H, Shiozaki M J Med Chem. 2020 Jun 8. doi: 10.1021/acs.jmedchem.0c00450. PMID:32511913<ref>PMID:32511913</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7c3n" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Adachi T]]
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[[Category: Non-specific protein-tyrosine kinase]]
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[[Category: Doi S]]
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[[Category: Adachi, T]]
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[[Category: Kikuwaka M]]
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[[Category: Doi, S]]
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[[Category: Noji S]]
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[[Category: Kikuwaka, M]]
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[[Category: Nomura A]]
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[[Category: Noji, S]]
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[[Category: Otira T]]
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[[Category: Nomura, A]]
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[[Category: Otira, T]]
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[[Category: Inhibitor]]
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[[Category: Transferase]]
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[[Category: Transferase-inihibitor complex]]

Revision as of 11:50, 22 July 2020

Crystal structure of JAK3 in complex with Delgocitinib

PDB ID 7c3n

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