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- PDB-6iuo: Crystal structure of FGFR4 kinase domain in complex with a covale... -

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Basic information

Entry
Database: PDB / ID: 6iuo
TitleCrystal structure of FGFR4 kinase domain in complex with a covalent inhibitor
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/INHIBITOR / protein kinase / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity / fibroblast growth factor binding / PI-3K cascade:FGFR4 / positive regulation of proteolysis / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / glucose homeostasis / PIP3 activates AKT signaling / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein autophosphorylation / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / Golgi apparatus / endoplasmic reticulum / extracellular region / ATP binding / plasma membrane
Similarity search - Function
Fibroblast growth factor receptor family / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype ...Fibroblast growth factor receptor family / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-AWX / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsXu, Y. / Liu, Q.
CitationJournal: J.Med.Chem. / Year: 2019
Title: 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.
Authors: 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. ...Authors: 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.
History
DepositionNov 29, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4182
Polymers35,9631
Non-polymers4541
Water91951
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13610 Å2
Unit cell
Length a, b, c (Å)138.716, 138.716, 49.814
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Fibroblast growth factor receptor 4 / / FGFR-4


Mass: 35963.375 Da / Num. of mol.: 1 / Fragment: UNP residues 445-753 / Mutation: R664E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4 / Production host: Escherichia coli (E. coli)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-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


Mass: 454.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 51 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.66 Å3/Da / Density % sol: 53.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1M HEPES pH7.5, 1.3 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 15826 / % possible obs: 99.5 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.113 / Net I/σ(I): 4.8
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.788 / % possible all: 98.8

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.06 Å46.01 Å
Translation5.06 Å46.01 Å

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASER2.7.16phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QQT

4qqt


Resolution: 2.3→50 Å / SU B: 7.558 / SU ML: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.287 / ESU R Free: 0.219 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.232 713 4.8 %RANDOM
Rwork0.186 ---
obs0.188 14106 93.4 %-
Displacement parametersBiso mean: 36.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20.01 Å20 Å2
2--0.03 Å20 Å2
3----0.09 Å2
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2116 0 34 51 2201

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