View source for 7tyd


==Crystal structure of FGFR4 domain 3 in complex with a de novo-designed mini-binder in P21 space group==
<StructureSection load='7tyd' size='340' side='right'caption='[[7tyd]], [[Resolution|resolution]] 2.86&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7tyd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TYD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TYD 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]] 2.86&#8491;</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=7tyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tyd OCA], [https://pdbe.org/7tyd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tyd RCSB], [https://www.ebi.ac.uk/pdbsum/7tyd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tyd 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 ==
Cellular signaling by fibroblast growth factor receptors (FGFRs) is a highly regulated process mediated by specific interactions between distinct subsets of fibroblast growth factor (FGF) ligands and two FGFR isoforms generated by alternative splicing: an epithelial b- and mesenchymal c-isoforms. Here, we investigate the properties of a mini-protein, mb7, developed by an in silico design strategy to bind to the ligand-binding region of FGFR2. We describe structural, biophysical, and cellular analyses demonstrating that mb7 binds with high affinity to the c-isoforms of FGFR, resulting in inhibition of cellular signaling induced by a subset of FGFs that preferentially activate c-isoforms of FGFR. Notably, as mb7 blocks interaction between FGFR with Klotho proteins, it functions as an antagonist of the metabolic hormones FGF19 and FGF21, providing mechanistic insights and strategies for the development of therapeutics for diseases driven by aberrantly activated FGFRs.

Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein.,Park JS, Choi J, Cao L, Mohanty J, Suzuki Y, Park A, Baker D, Schlessinger J, Lee S Cell Rep. 2022 Oct 25;41(4):111545. doi: 10.1016/j.celrep.2022.111545. PMID:36288716<ref>PMID:36288716</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7tyd" 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: Synthetic construct]]
[[Category: Lee S]]
[[Category: Park JS]]