View source for 4tyi


==Structural analysis of the human Fibroblast Growth Factor Receptor 4==
<StructureSection load='4tyi' size='340' side='right'caption='[[4tyi]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tyi]] 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=4TYI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TYI 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]] 3.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38O:4-AMINO-5-FLUORO-3-[5-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL]QUINOLIN-2(1H)-ONE'>38O</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=4tyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tyi OCA], [https://pdbe.org/4tyi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tyi RCSB], [https://www.ebi.ac.uk/pdbsum/4tyi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tyi ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FGFR4_HUMAN FGFR4_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.<ref>PMID:7680645</ref> <ref>PMID:7518429</ref> <ref>PMID:8663044</ref> <ref>PMID:11433297</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:18670643</ref> <ref>PMID:20683963</ref> <ref>PMID:20018895</ref> <ref>PMID:20798051</ref> <ref>PMID:21653700</ref> <ref>PMID:20876804</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The family of Fibroblast Growth Factor Receptors (FGFRs) plays an important and well characterized role in a variety of pathological disorders. FGFR4 is involved in myogenesis and muscle regeneration. Mutations affecting the kinase domain of FGFR4 may cause cancer e.g. breast cancer or rhabdomyosarcoma. Whereas FGFRs 1-3 have been structurally characterized, the structure of the FGFR4 kinase domain has not yet been reported. In this study we present four structures of the kinase domain of FGFR4, in its apo-form and in complex with different types of small-molecule inhibitors. The two apo-FGFR4 kinase domain structures show an activation segment similar in conformation to an autoinhibitory segment observed in the hepatocyte growth factor receptor kinase but different from the known structures of other FGFR kinases. The structures of FGFR4 in complex with the type I-inhibitor Dovitinib and the type II-inhibitor Ponatinib reveal the molecular interactions with different types of kinase inhibitors and may assist in the design and development of FGFR4-inhibitors.

Structural analysis of the human Fibroblast Growth Factor Receptor 4 Kinase.,Lesca E, Lammens A, Huber R, Augustin M J Mol Biol. 2014 Sep 11. pii: S0022-2836(14)00474-4. doi:, 10.1016/j.jmb.2014.09.004. PMID:25219510<ref>PMID:25219510</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tyi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fibroblast growth factor receptor 3D receptor|Fibroblast growth factor receptor 3D receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Augustin M]]
[[Category: Huber R]]
[[Category: Lammens A]]
[[Category: Lesca E]]