6iuo
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of FGFR4 kinase domain in complex with a covalent inhibitor== | |
| + | <StructureSection load='6iuo' size='340' side='right'caption='[[6iuo]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6iuo]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IUO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IUO FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AWX:N-({4-[4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-2-yl]phenyl}methyl)prop-2-enamide'>AWX</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=6iuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6iuo OCA], [http://pdbe.org/6iuo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6iuo RCSB], [http://www.ebi.ac.uk/pdbsum/6iuo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6iuo ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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 == | ||
| + | Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery. | ||
| - | + | Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design.,Wang Y, Dai Y, Wu X, Li F, Liu B, Li C, Liu Q, Zhou Y, Wang B, Zhu M, Cui R, Tan X, Xiong Z, Liu J, Tan M, Xu Y, Geng M, Jiang H, Liu H, Ai J, Zheng M J Med Chem. 2019 Aug 22;62(16):7473-7488. doi: 10.1021/acs.jmedchem.9b00510. Epub, 2019 Aug 9. PMID:31335138<ref>PMID:31335138</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Liu, Q | + | <div class="pdbe-citations 6iuo" style="background-color:#fffaf0;"></div> |
| - | [[Category: Xu, Y | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Receptor protein-tyrosine kinase]] | ||
| + | [[Category: Liu, Q]] | ||
| + | [[Category: Xu, Y]] | ||
| + | [[Category: Protein kinase]] | ||
| + | [[Category: Transferase-inhibitor complex]] | ||
Revision as of 06:48, 23 October 2019
Crystal structure of FGFR4 kinase domain in complex with a covalent inhibitor
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