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7uy0

From Proteopedia

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Current revision

Crystal structure of human Fgr tyrosine kinase in complex with A-419259

Structural highlights

7uy0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.55Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FGR_HUMAN Mutations that cause aberrant kinase activation can confer oncogene activity and promote aberrant cell proliferation.

Function

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 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 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]^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Axelsson L, Hellberg C, Melander F, Smith D, Zheng L, Andersson T. Clustering of beta(2)-integrins on human neutrophils activates dual signaling pathways to PtdIns 3-kinase. Exp Cell Res. 2000 Apr 10;256(1):257-63. doi: 10.1006/excr.2000.4816. PMID:10739672 doi:http://dx.doi.org/10.1006/excr.2000.4816
↑ Zuccato E, Blott EJ, Holt O, Sigismund S, Shaw M, Bossi G, Griffiths GM. Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation. J Cell Sci. 2007 Jan 1;120(Pt 1):191-9. doi: 10.1242/jcs.03315. Epub 2006 Dec 12. PMID:17164290 doi:http://dx.doi.org/10.1242/jcs.03315
↑ Sartor O, Moriuchi R, Sameshima JH, Severino M, Gutkind JS, Robbins KC. Diverse biologic properties imparted by the c-fgr proto-oncogene. J Biol Chem. 1992 Feb 15;267(5):3460-5. PMID:1737799
↑ Berton G, Fumagalli L, Laudanna C, Sorio C. Beta 2 integrin-dependent protein tyrosine phosphorylation and activation of the FGR protein tyrosine kinase in human neutrophils. J Cell Biol. 1994 Aug;126(4):1111-21. doi: 10.1083/jcb.126.4.1111. PMID:7519620 doi:http://dx.doi.org/10.1083/jcb.126.4.1111
↑ Du S, Alvarado JJ, Wales TE, Moroco JA, Engen JR, Smithgall TE. ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr. Structure. 2022 Nov 3;30(11):1508-1517.e3. doi: 10.1016/j.str.2022.08.008. Epub , 2022 Sep 16. PMID:36115344 doi:http://dx.doi.org/10.1016/j.str.2022.08.008

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7uy0"

Categories: Homo sapiens | Large Structures | Alvarado JJ | Du S | Smithgall TE

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7uy0]] 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=7UY0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UY0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=VSE:7-[TRANS-4-(4-METHYLPIPERAZIN-1-YL)CYCLOHEXYL]-5-(4-PHENOXYPHENYL)-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>VSE</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=VSE:7-[TRANS-4-(4-METHYLPIPERAZIN-1-YL)CYCLOHEXYL]-5-(4-PHENOXYPHENYL)-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>VSE</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=7uy0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uy0 OCA], [https://pdbe.org/7uy0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uy0 RCSB], [https://www.ebi.ac.uk/pdbsum/7uy0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uy0 ProSAT]</span></td></tr>
 </table>

7uy0

From Proteopedia

Current revision

Crystal structure of human Fgr tyrosine kinase in complex with A-419259

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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