7apf: Difference between revisions

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==Crystal structure of JAK3 in complex with FM601 (compound 10a)==
==Crystal structure of JAK3 in complex with FM601 (compound 10a)==
<StructureSection load='7apf' size='340' side='right'caption='[[7apf]]' scene=''>
<StructureSection load='7apf' size='340' side='right'caption='[[7apf]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7APF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7APF FirstGlance]. <br>
<table><tr><td colspan='2'>[[7apf]] 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=7APF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7APF FirstGlance]. <br>
</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=7apf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apf OCA], [http://pdbe.org/7apf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7apf RCSB], [http://www.ebi.ac.uk/pdbsum/7apf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7apf ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PHU:1-PHENYLUREA'>PHU</scene>, <scene name='pdbligand=RQZ:3-[3-(propanoylamino)phenyl]-1~{H}-pyrrolo[2,3-b]pyridine-5-carboxamide'>RQZ</scene></td></tr>
<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>
<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://proteopedia.org/fgij/fg.htm?mol=7apf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apf OCA], [http://pdbe.org/7apf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7apf RCSB], [http://www.ebi.ac.uk/pdbsum/7apf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7apf ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[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> 
== Function ==
[[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The nonreceptor tyrosine TEC kinases are key regulators of the immune system and play a crucial role in the pathogenesis of diverse hematological malignancies. In contrast to the substantial efforts in inhibitor development for Bruton's tyrosine kinase (BTK), specific inhibitors of the other TEC kinases, including the bone marrow tyrosine kinase on chromosome X (BMX), remain sparse. Here we present a novel class of dual BMX/BTK inhibitors, which were designed from irreversible inhibitors of Janus kinase (JAK) 3 targeting a cysteine located within the solvent-exposed front region of the ATP binding pocket. Structure-guided design exploiting the differences in the gatekeeper residues enabled the achievement of high selectivity over JAK3 and certain other kinases harboring a sterically demanding residue at this position. The most active compounds inhibited BMX and BTK with apparent IC50 values in the single digit nanomolar range or below showing moderate selectivity within the TEC family and potent cellular target engagement. These compounds represent an important first step towards selective chemical probes for the protein kinase BMX.
Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.,Forster M, Liang XJ, Schroder M, Gerstenecker S, Chaikuad A, Knapp S, Laufer S, Gehringer M Int J Mol Sci. 2020 Dec 4;21(23). pii: ijms21239269. doi: 10.3390/ijms21239269. PMID:33291717<ref>PMID:33291717</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7apf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chaikuad A]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Forster M]]
[[Category: Chaikuad, A]]
[[Category: Gehringer M]]
[[Category: Forster, M]]
[[Category: Knapp S]]
[[Category: Gehringer, M]]
[[Category: Laufer S]]
[[Category: Knapp, S]]
[[Category: Laufer, S]]
[[Category: Structural genomic]]
[[Category: Covalent inhibitor]]
[[Category: Inhibitor]]
[[Category: Jak3]]
[[Category: Kinase]]
[[Category: Sgc]]
[[Category: Transferase]]

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