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| | ==Crystal Structure of Beta-Klotho in Complex with FGF21CT== | | ==Crystal Structure of Beta-Klotho in Complex with FGF21CT== |
| - | <StructureSection load='5vaq' size='340' side='right' caption='[[5vaq]], [[Resolution|resolution]] 2.61Å' scene=''> | + | <StructureSection load='5vaq' size='340' side='right'caption='[[5vaq]], [[Resolution|resolution]] 2.61Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5vaq]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VAQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VAQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5vaq]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VAQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.606Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v9q|5v9q]], [[5v9r|5v9r]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5vaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vaq OCA], [http://pdbe.org/5vaq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vaq RCSB], [http://www.ebi.ac.uk/pdbsum/5vaq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vaq ProSAT]</span></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=5vaq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vaq OCA], [https://pdbe.org/5vaq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vaq RCSB], [https://www.ebi.ac.uk/pdbsum/5vaq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vaq ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KLOTB_HUMAN KLOTB_HUMAN]] Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity). [[http://www.uniprot.org/uniprot/FGF21_HUMAN FGF21_HUMAN]] Stimulates glucose uptake in differentiated adipocytes via the induction of glucose transporter SLC2A1/GLUT1 expression (but not SLC2A4/GLUT4 expression). Activity requires the presence of KLB.<ref>PMID:15902306</ref> <ref>PMID:17623664</ref> | + | [https://www.uniprot.org/uniprot/KLOTB_HUMAN KLOTB_HUMAN] Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5vaq" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5vaq" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Fibroblast growth factor 3D structures|Fibroblast growth factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lee, S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Schlessinger, J]] | + | [[Category: Lama glama]] |
| - | [[Category: Signaling protein]] | + | [[Category: Large Structures]] |
| | + | [[Category: Lee S]] |
| | + | [[Category: Schlessinger J]] |
| Structural highlights
Function
KLOTB_HUMAN Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity).
Publication Abstract from PubMed
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound beta-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards beta-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. beta-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.
Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.,Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, Steyaert J, Lemmon MA, Lax I, Schlessinger J Nature. 2018 Jan 25;553(7689):501-505. doi: 10.1038/nature25010. Epub 2018 Jan, 17. PMID:29342135[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, Steyaert J, Lemmon MA, Lax I, Schlessinger J. Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling. Nature. 2018 Jan 25;553(7689):501-505. doi: 10.1038/nature25010. Epub 2018 Jan, 17. PMID:29342135 doi:http://dx.doi.org/10.1038/nature25010
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