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- PDB-8xlq: FGFR4 kinase domain with a dual-warhead covalent inhibitor CXF-007 -

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Basic information

Entry
Database: PDB / ID: 8xlq
TitleFGFR4 kinase domain with a dual-warhead covalent inhibitor CXF-007
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/INHIBITOR / Fibroblast growth factor receptor 4 / 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: 1.95 Å
AuthorsChen, X.J. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82202920 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Design, synthesis, and biological evaluation of selective covalent inhibitors of FGFR4.
Authors: Chen, X. / Li, H. / Lin, Q. / Dai, S. / Qu, L. / Guo, M. / Zhang, L. / Liao, J. / Wei, H. / Xu, G. / Jiang, L. / Chen, Y.
History
DepositionDec 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 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)35,6035
Polymers34,6951
Non-polymers9084
Water3,621201
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)41.880, 61.100, 61.060
Angle α, β, γ (deg.)90.000, 97.980, 90.000
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Escherichia coli #1/H766 (bacteria)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1LVQ / CXF007 / ~{N}-[4-[2-[3-(3,5-dimethoxyphenyl)-2-oxidanylidene-7-[[2-(prop-2-enoylamino)phenyl]amino]-4~{H}-pyrimido[4,5-d]pyrimidin-1-yl]ethyl]phenyl]propanamide


Mass: 619.670 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H33N7O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.23 Å3/Da / Density % sol: 44.84 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris (pH 4.5), 0.2 M Li2SO4, 16-20% PEG3350

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.95→60.47 Å / Num. obs: 22227 / % possible obs: 99.24 % / Redundancy: 6.3 % / Biso Wilson estimate: 27.73 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.08815 / Net I/σ(I): 14.1
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.554 / Mean I/σ(I) obs: 2.47 / Num. unique obs: 2210 / CC1/2: 0.876 / % possible all: 97.91

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7V29

7v29


Resolution: 1.95→60.468 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2106 1999 9 %
Rwork0.1668 20219 -
obs0.1708 22218 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 103.93 Å2 / Biso mean: 36.4847 Å2 / Biso min: 16.29 Å2
Refinement stepCycle: final / Resolution: 1.95→60.468 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2328 0 61 201 2590
Biso mean--42.38 41.13 -
Num. residues----296
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012451
X-RAY DIFFRACTIONf_angle_d1.143328
X-RAY DIFFRACTIONf_chiral_restr0.051350
X-RAY DIFFRACTIONf_plane_restr0.006431
X-RAY DIFFRACTIONf_dihedral_angle_d14.184914
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.95-1.99880.31641440.2659144798
1.9988-2.05280.33281370.2305139198
2.0528-2.11320.26161420.2137143598
2.1132-2.18150.25151410.1871142499
2.1815-2.25940.23581410.1779143499
2.2594-2.34990.2341430.1707144399
2.3499-2.45680.21561420.16711441100
2.4568-2.58640.26251430.17061440100
2.5864-2.74840.2321440.17641453100
2.7484-2.96060.21961420.17541445100
2.9606-3.25850.20991440.17021447100
3.2585-3.730.19611430.1531457100
3.73-4.69910.1721480.13591484100
4.6991-60.460.17071450.1594147899

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