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- PDB-8kh6: Crystal structure of FGFR4 kinase domain with 8r -

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Basic information

Entry
Database: PDB / ID: 8kh6
TitleCrystal structure of FGFR4 kinase domain with 8r
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/INHIBITOR / complex / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 / fibroblast growth factor binding / regulation of lipid metabolic process / positive regulation of proteolysis / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / peptidyl-tyrosine phosphorylation / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / glucose homeostasis / PIP3 activates AKT signaling / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / endoplasmic reticulum / Golgi apparatus / 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / 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: 1.62 Å
AuthorsLin, Q.M. / Chen, X.J. / Chen, Y.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
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 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)35,4214
Polymers34,6951
Non-polymers7263
Water2,378132
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.780, 61.180, 60.720
Angle α, β, γ (deg.)90.00, 97.76, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 34695.059 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: R222E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Escherichia coli (E. coli)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-VVI / 1-[4-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-3-[5-bromanyl-6-(hydroxymethyl)-3-methoxy-pyridin-2-yl]urea


Mass: 568.207 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17BrCl2N6O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.22 Å3/Da / Density % sol: 44.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris (pH 4.5), 0.2 M Li2SO4, 16-19% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 2, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.62→27.27 Å / Num. obs: 37228 / % possible obs: 96.23 % / Redundancy: 6.2 % / CC1/2: 0.999 / Net I/σ(I): 14.8
Reflection shellResolution: 1.62→7.24 Å / Num. unique obs: 37169 / CC1/2: 0.999

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7YBO

7ybo


Resolution: 1.62→27.27 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2276 1997 5.37 %
Rwork0.2037 --
obs0.205 37168 96.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.62→27.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2237 0 43 132 2412
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072336
X-RAY DIFFRACTIONf_angle_d0.9663175
X-RAY DIFFRACTIONf_dihedral_angle_d7.625334
X-RAY DIFFRACTIONf_chiral_restr0.062346
X-RAY DIFFRACTIONf_plane_restr0.01409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62-1.660.43161040.42561841X-RAY DIFFRACTION71
1.66-1.710.38351200.37412091X-RAY DIFFRACTION81
1.71-1.760.33961450.312549X-RAY DIFFRACTION97
1.76-1.810.29391480.26592608X-RAY DIFFRACTION100
1.81-1.880.29951460.23872555X-RAY DIFFRACTION99
1.88-1.950.26051480.21812601X-RAY DIFFRACTION100
1.95-2.040.23081460.19122582X-RAY DIFFRACTION100
2.04-2.150.21151460.18662598X-RAY DIFFRACTION100
2.15-2.280.23381470.20332603X-RAY DIFFRACTION100
2.28-2.460.20991500.20752635X-RAY DIFFRACTION100
2.46-2.710.2611470.20962580X-RAY DIFFRACTION100
2.71-3.10.24161490.20912633X-RAY DIFFRACTION100
3.1-3.90.19981500.18652630X-RAY DIFFRACTION100
3.9-27.270.19991510.18262665X-RAY DIFFRACTION100

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