View source for 10fv


==Crystal Structure of Human Fgr SH3-SH2-High Affinity Linker Mutant 2 (HAL2) Domains.==
<StructureSection load='10fv' size='340' side='right'caption='[[10fv]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[10fv]] 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=10FV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=10FV 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=10fv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=10fv OCA], [https://pdbe.org/10fv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=10fv RCSB], [https://www.ebi.ac.uk/pdbsum/10fv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=10fv 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 ==
Acute myeloid leukemia is often associated with constitutive activation of the Src-family kinases, Hck, Lyn, and Fgr. Their modular SH3 and SH2 domains regulate kinase activity and signal transduction. Here, we show that regulatory domain dynamics critically influence both inhibitor sensitivity and leukemogenic signaling. We modified the Fgr SH2-kinase linker to enhance intramolecular SH3 engagement, shifting the conformational ensemble to the closed state. This shift increased the K(m) for ATP and enhanced the potency of ATP-site inhibitors in vitro. Human myeloid cells expressing these constrained Fgr variants exhibited heightened sensitivity to ATP-site inhibitors in terms of growth arrest. These cells also demonstrated impaired bone marrow engraftment in vivo, suggesting a key role for Fgr dynamics and SH3-dependent signaling in leukemia cell survival within this niche. Small molecules that similarly restrict Src-family kinase regulatory domain dynamics may provide a new therapeutic approach to AML and other cancers linked to these kinases.

Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.,Gonzalez-Areizaga G, Shu ST, Alvarado JJ, Shi H, Chen L, Smithgall TE Cell Rep. 2026 Jun 23;45(6):117551. doi: 10.1016/j.celrep.2026.117551. Epub 2026 , Jun 16. PMID:42301812<ref>PMID:42301812</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 10fv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Alvarado JJ]]
[[Category: Gonzalez-Areizaga G]]
[[Category: Smithgall TE]]