7uy3: Difference between revisions
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==Crystal structure of human Fgr tyrosine kinase in complex with TL02-59== | |||
<StructureSection load='7uy3' size='340' side='right'caption='[[7uy3]], [[Resolution|resolution]] 2.99Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7uy3]] 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=7UY3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UY3 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]] 2.99Å</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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OJL:3-(6,7-dimethoxyquinazolin-4-yl)oxy-~{N}-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-benzamide'>OJL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=7uy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uy3 OCA], [https://pdbe.org/7uy3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uy3 RCSB], [https://www.ebi.ac.uk/pdbsum/7uy3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uy3 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/FGR_HUMAN FGR_HUMAN] Mutations that cause aberrant kinase activation can confer oncogene activity and promote aberrant cell proliferation. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/FGR_HUMAN FGR_HUMAN] Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration. Promotes mast cell degranulation, release of inflammatory cytokines and IgE-mediated anaphylaxis. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as MS4A2/FCER1B, FCGR2A and/or FCGR2B. Acts downstream of ITGB1 and ITGB2, and regulates actin cytoskeleton reorganization, cell spreading and adhesion. Depending on the context, activates or inhibits cellular responses. Functions as a negative regulator of ITGB2 signaling, phagocytosis and SYK activity in monocytes. Required for normal ITGB1 and ITGB2 signaling, normal cell spreading and adhesion in neutrophils and macrophages. Functions as a positive regulator of cell migration and regulates cytoskeleton reorganization via RAC1 activation. Phosphorylates SYK (in vitro) and promotes SYK-dependent activation of AKT1 and MAP kinase signaling. Phosphorylates PLD2 in antigen-stimulated mast cells, leading to PLD2 activation and the production of the signaling molecules lysophosphatidic acid and diacylglycerol. Promotes activation of PIK3R1. Phosphorylates FASLG, and thereby regulates its ubiquitination and subsequent internalization. Phosphorylates ABL1. Promotes phosphorylation of CBL, CTTN, PIK3R1, PTK2/FAK1, PTK2B/PYK2 and VAV2. Phosphorylates HCLS1 that has already been phosphorylated by SYK, but not unphosphorylated HCLS1. Together with CLNK, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production (By similarity).[UniProtKB:P14234]<ref>PMID:10739672</ref> <ref>PMID:17164290</ref> <ref>PMID:1737799</ref> <ref>PMID:7519620</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Src-family kinase Fgr is expressed primarily in myeloid hematopoietic cells and contributes to myeloid leukemia. Here, we present X-ray crystal structures of Fgr bound to the ATP-site inhibitors A-419259 and TL02-59, which show promise as anti-leukemic agents. A-419259 induces a closed Fgr conformation, with the SH3 and SH2 domains engaging the SH2-kinase linker and C-terminal tail, respectively. In the Fgr:A-419259 complex, the activation loop of one monomer inserts into the active site of the other, providing a snapshot of trans-autophosphorylation. By contrast, TL02-59 binding induced SH2 domain displacement from the C-terminal tail and SH3 domain release from the linker. Solution studies using HDX MS were consistent with the crystal structures, with A-419259 reducing and TL02-59 enhancing solvent exposure of the SH3 domain. These structures demonstrate that allosteric connections between the kinase and regulatory domains of Src-family kinases are regulated by the ligand bound to the active site. | |||
ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.,Du S, Alvarado JJ, Wales TE, Moroco JA, Engen JR, Smithgall TE Structure. 2022 Nov 3;30(11):1508-1517.e3. doi: 10.1016/j.str.2022.08.008. Epub , 2022 Sep 16. PMID:36115344<ref>PMID:36115344</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7uy3" style="background-color:#fffaf0;"></div> | ||
[[Category: Alvarado | |||
[[Category: Du | ==See Also== | ||
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Alvarado JJ]] | |||
[[Category: Du S]] | |||
[[Category: Smithgall TE]] | |||