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- PDB-8kh9: Crystal structure of FGFR4(V550M) kinase domain with 8z -

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Basic information

Entry
Database: PDB / ID: 8kh9
TitleCrystal structure of FGFR4(V550M) kinase domain with 8z
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/INHIBITOR / inhibitor / FGFR4 / 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: 1.42 Å
AuthorsLin, Q.M. / Chen, X.J. / Chen, Y.H.
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 21, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,5304
Polymers33,6591
Non-polymers8713
Water6,305350
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)42.398, 61.605, 60.605
Angle α, β, γ (deg.)90.00, 97.93, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Fibroblast growth factor receptor 4


Mass: 33658.836 Da / Num. of mol.: 1 / Mutation: C477A,V550M,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
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-VVW / 1-[4-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-3-[6-methanoyl-5-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3-(2-morpholin-4-ylethoxy)pyridin-2-yl]urea


Mass: 712.583 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C32H35Cl2N9O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 2.33 Å3/Da / Density % sol: 47.19 %
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: 277 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.42→61.6 Å / Num. obs: 58347 / % possible obs: 100 % / Redundancy: 6 % / CC1/2: 0.996 / Net I/σ(I): 10.3
Reflection shellResolution: 1.42→1.46 Å / Num. unique obs: 4290 / CC1/2: 0.194

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Processing

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

7wcx


Resolution: 1.42→36.88 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1926 2868 4.93 %
Rwork0.1698 --
obs0.1709 58191 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.42→36.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2328 0 58 350 2736
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092449
X-RAY DIFFRACTIONf_angle_d1.0833329
X-RAY DIFFRACTIONf_dihedral_angle_d16.386345
X-RAY DIFFRACTIONf_chiral_restr0.095354
X-RAY DIFFRACTIONf_plane_restr0.012432
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.42-1.440.31791610.27382710X-RAY DIFFRACTION98
1.44-1.470.2331320.24122742X-RAY DIFFRACTION99
1.47-1.50.28071130.21752762X-RAY DIFFRACTION100
1.5-1.530.22921410.21732750X-RAY DIFFRACTION100
1.53-1.560.25121280.21652787X-RAY DIFFRACTION100
1.56-1.60.20151360.20072730X-RAY DIFFRACTION100
1.6-1.640.22811420.18982789X-RAY DIFFRACTION100
1.64-1.680.23131530.18432726X-RAY DIFFRACTION100
1.68-1.730.22871480.17272755X-RAY DIFFRACTION100
1.73-1.790.20361390.16622777X-RAY DIFFRACTION100
1.79-1.850.20541460.16992758X-RAY DIFFRACTION100
1.85-1.930.19141450.17262776X-RAY DIFFRACTION100
1.93-2.010.20791580.16692772X-RAY DIFFRACTION100
2.01-2.120.18891670.15562729X-RAY DIFFRACTION100
2.12-2.250.19711290.16072780X-RAY DIFFRACTION100
2.25-2.430.17541610.16042761X-RAY DIFFRACTION100
2.43-2.670.19781410.16832794X-RAY DIFFRACTION100
2.67-3.060.20341360.16962781X-RAY DIFFRACTION100
3.06-3.850.161380.1492824X-RAY DIFFRACTION100
3.85-36.880.15441540.15822820X-RAY DIFFRACTION100

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