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- PDB-6iup: Crystal structure of FGFR4 kinase domain in complex with compound 5 -

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Basic information

Entry
Database: PDB / ID: 6iup
TitleCrystal structure of FGFR4 kinase domain in complex with compound 5
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 / 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. / 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 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-AX0 / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 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 1.0Nov 6, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)36,4823
Polymers35,9631
Non-polymers5192
Water4,972276
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint4 kcal/mol
Surface area14470 Å2
Unit cell
Length a, b, c (Å)42.400, 61.150, 61.400
Angle α, β, γ (deg.)90.000, 99.220, 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: 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-AX0 / 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}prop-2-enamide


Mass: 440.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H20N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6OS / Feature type: SUBJECT OF INVESTIGATION / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 276 / 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: 2.27 Å3/Da / Density % sol: 45.77 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1M MES pH5.5, 0.2M Li2SO4, 18% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2→32.118 Å / Num. obs: 40623 / % possible obs: 98.7 % / Redundancy: 2.143 % / Biso Wilson estimate: 16.64 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.07 / Rrim(I) all: 0.094 / Χ2: 1.026 / Net I/σ(I): 10.38 / Num. measured all: 87038
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2-2.052.1330.2972.886464306530310.8540.39298.9
2.05-2.112.130.253.446289297329520.890.33199.3
2.11-2.172.1390.2044.166049285628280.9240.26999
2.17-2.242.1280.1914.55977283028090.9290.25399.3
2.24-2.312.1420.175.175710267926660.9490.22599.5
2.31-2.392.1330.1455.925524261125900.9570.19299.2
2.39-2.482.1320.1346.585508260025830.9610.17899.3
2.48-2.582.1420.1197.225048239423570.9660.15898.5
2.58-2.72.150.0968.595021236023350.980.12898.9
2.7-2.832.1440.083104714223321990.9830.11198.5
2.83-2.982.140.06612.044538214321210.9890.08899
2.98-3.162.1310.05713.264182199619620.9920.07698.3
3.16-3.382.1320.04816.683971189418630.9930.06498.4
3.38-3.652.1320.03819.463629174617020.9960.0597.5
3.65-42.0980.03421.523338162115910.9960.04598.1
4-4.472.1950.0324.063122144814220.9970.0498.2
4.47-5.162.1960.03123.812848131212970.9960.04298.9
5.16-6.322.210.03422.472356109410660.9950.04697.4
6.32-8.942.2010.02924.9717818358090.9970.03996.9
8.94-32.1182.2020.02431.929694704400.9980.03293.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.5 Å34.54 Å
Translation5.5 Å34.54 Å

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Processing

Software
NameVersionClassification
PHENIXv1.0refinement
XDSdata reduction
XSCALEdata scaling
PHASER2.7.16phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QQT

4qqt


Resolution: 2→32.118 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0.96 / Phase error: 21.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2277 2025 4.99 %
Rwork0.1694 38593 -
obs0.1724 40618 98.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 62.69 Å2 / Biso mean: 19.5483 Å2 / Biso min: 6.3 Å2
Refinement stepCycle: final / Resolution: 2→32.118 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2239 0 37 276 2552
Biso mean--21.44 25.66 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072344
X-RAY DIFFRACTIONf_angle_d0.8433187
X-RAY DIFFRACTIONf_chiral_restr0.057345
X-RAY DIFFRACTIONf_plane_restr0.005410
X-RAY DIFFRACTIONf_dihedral_angle_d19.8671405
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2-2.04990.22581450.1854279699
2.0499-2.10530.27691470.192276299
2.1053-2.16720.25591400.1909273699
2.1672-2.23720.28491500.1921279199
2.2372-2.31710.23491420.1774273599
2.3171-2.40990.23171470.17279699
2.4099-2.51950.24051440.1679274799
2.5195-2.65230.21521490.1778281599
2.6523-2.81840.24641440.1799270899
2.8184-3.03580.22811420.1789275999
3.0358-3.3410.22181440.168274998
3.341-3.82380.19041460.1514274998
3.8238-4.8150.19731460.141273099
4.815-100.24041390.1726272097

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