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- PDB-8w5c: Crystal structure of FGFR4 kinase domain in complex with 8K -

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Basic information

Entry
Database: PDB / ID: 8w5c
TitleCrystal structure of FGFR4 kinase domain in complex with 8K
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / TRANSFERASE-Inhibitor complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / fibroblast growth factor receptor activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / positive regulation of catalytic activity / positive regulation of DNA biosynthetic process ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / fibroblast growth factor receptor activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / positive regulation of catalytic activity / positive regulation of DNA biosynthetic process / 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 / FRS-mediated FGFR4 signaling / transport vesicle / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / glucose homeostasis / 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. ...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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / 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
Similarity search - Domain/homology
: / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhang, Z.M. / Huang, H.S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.
Authors: Yang, F. / Lin, Q. / Song, X. / Huang, H. / Chen, X. / Tan, J. / Li, Y. / Zhou, Y. / Tu, Z. / Du, H. / Zhang, Z.M. / Ortega, R. / Lin, X. / Patterson, A.V. / Smaill, J.B. / Chen, Y. / Lu, X.
History
DepositionAug 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,3834
Polymers67,3462
Non-polymers1,0372
Water3,027168
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.831, 61.799, 181.621
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Fibroblast growth factor receptor 4


Mass: 33672.891 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-VZO / N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-5-methanoyl-6-[(4-methylpiperazin-1-yl)methyl]-1-propan-2-yl-pyrrolo[3,2-b]pyridine-3-carboxamide


Mass: 518.611 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H34N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.58 Å3/Da / Density % sol: 52.26 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: Na citrate ph 5.5, (NH4)2SO4 1.4M

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CAMD / Beamline: GCPCC / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.3→55 Å / Num. obs: 31513 / % possible obs: 95.26 % / Redundancy: 2.383 % / Biso Wilson estimate: 41.08 Å2 / CC1/2: 0.99 / Net I/σ(I): 7.1
Reflection shellResolution: 2.301→2.383 Å / Num. unique obs: 30990 / CC1/2: 0.992

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→27.64 Å / SU ML: 0.2994 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.6801
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.264 1966 6.35 %
Rwork0.2286 28993 -
obs0.2308 30959 97.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.71 Å2
Refinement stepCycle: LAST / Resolution: 2.3→27.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4126 0 76 168 4370
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00334306
X-RAY DIFFRACTIONf_angle_d0.66115848
X-RAY DIFFRACTIONf_chiral_restr0.0424641
X-RAY DIFFRACTIONf_plane_restr0.0047747
X-RAY DIFFRACTIONf_dihedral_angle_d14.14181590
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.36061350.2681956X-RAY DIFFRACTION94.87
2.36-2.420.3231340.27661973X-RAY DIFFRACTION95.3
2.42-2.490.33211310.27932026X-RAY DIFFRACTION96.55
2.49-2.570.371380.27182020X-RAY DIFFRACTION96.68
2.57-2.670.32631380.25192013X-RAY DIFFRACTION96.54
2.67-2.770.29461410.26062024X-RAY DIFFRACTION97.3
2.77-2.90.32661420.24942062X-RAY DIFFRACTION98.04
2.9-3.050.281420.25282076X-RAY DIFFRACTION99.06
3.05-3.240.27281420.24732107X-RAY DIFFRACTION99.16
3.24-3.490.26521440.23082102X-RAY DIFFRACTION99.42
3.49-3.840.26631470.21162125X-RAY DIFFRACTION99.43
3.84-4.40.22221460.19872127X-RAY DIFFRACTION99.47
4.4-5.530.21561400.20692169X-RAY DIFFRACTION99.35
5.53-27.640.24341460.21992213X-RAY DIFFRACTION96.76

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