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| | <StructureSection load='6nfj' size='340' side='right'caption='[[6nfj]], [[Resolution|resolution]] 3.19Å' scene=''> | | <StructureSection load='6nfj' size='340' side='right'caption='[[6nfj]], [[Resolution|resolution]] 3.19Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nfj]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Camelus_glama Camelus glama] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NFJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NFJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nfj]] is a 6 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=6NFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NFJ FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 3.19Å</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=6nfj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nfj OCA], [http://pdbe.org/6nfj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nfj RCSB], [http://www.ebi.ac.uk/pdbsum/6nfj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nfj 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=6nfj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nfj OCA], [https://pdbe.org/6nfj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nfj RCSB], [https://www.ebi.ac.uk/pdbsum/6nfj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nfj 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/FGF19_HUMAN FGF19_HUMAN]] Involved in the suppression of bile acid biosynthesis through down-regulation of CYP7A1 expression, following positive regulation of the JNK and ERK1/2 cascades. Stimulates glucose uptake in adipocytes. Activity requires the presence of KLB and FGFR4.<ref>PMID:12815072</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:19085950</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 6nfj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6nfj" 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: Camelus glama]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Lama glama]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kuzina, E]] | + | [[Category: Kuzina E]] |
| - | [[Category: Lee, S]] | + | [[Category: Lee S]] |
| - | [[Category: Schlessinger, J]] | + | [[Category: Schlessinger J]] |
| - | [[Category: Fgf19]]
| + | |
| - | [[Category: Klotho]]
| + | |
| - | [[Category: Nanobody]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Signaling]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| 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
The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either alpha-Klotho or beta-Klotho receptors. Structural analyses of ligand-occupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to beta-Klotho or alpha-Klotho, respectively. They have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling. Here we describe the crystal structure the C-terminal tail of FGF19 (FGF19CT) bound to sKLB and demonstrate that FGF19CT and FGF21CT bind to the same binding site on sKLB, via a multiturn D-P motif to site 1 and via a S-P-S motif to the pseudoglycoside hydrolase region (site 2). Binding affinities to sKLB and cellular stimulatory activities of FGF19CT, FGF21CT, and a variety of chimeric mutants to cells expressing beta-Klotho together with FGFR1c or FGFR4 were also analyzed. These experiments as well as detailed comparison of the structures of free and ligand-occupied sKLB to the structure of ligand-occupied sKLA reveal a general mechanism for recognition of endocrine FGFs by Klotho proteins and regulatory interactions with FGFRs that control their pleiotropic cellular responses.
Structures of ligand-occupied beta-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity.,Kuzina ES, Ung PM, Mohanty J, Tome F, Choi J, Pardon E, Steyaert J, Lax I, Schlessinger A, Schlessinger J, Lee S Proc Natl Acad Sci U S A. 2019 Apr 3. pii: 1822055116. doi:, 10.1073/pnas.1822055116. PMID:30944224[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kuzina ES, Ung PM, Mohanty J, Tome F, Choi J, Pardon E, Steyaert J, Lax I, Schlessinger A, Schlessinger J, Lee S. Structures of ligand-occupied beta-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity. Proc Natl Acad Sci U S A. 2019 Apr 3. pii: 1822055116. doi:, 10.1073/pnas.1822055116. PMID:30944224 doi:http://dx.doi.org/10.1073/pnas.1822055116
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