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- PDB-4xcu: Crystal Structure of FGFR4 with an Irreversible Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4xcu
TitleCrystal Structure of FGFR4 with an Irreversible Inhibitor
ComponentsFibroblast growth factor receptor 4
KeywordsTransferase/Transferase Inhibitor / Receptor Tyrosine Kinase / Hepatocellular carcinoma / Transferase-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-40M / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.71 Å
AuthorsKim, J.L. / Miduturu, C. / Hodous, B. / Brooijmans, N. / Bifulco, N. / Guzi, T.
CitationJournal: Cancer Discov / Year: 2015
Title: First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway.
Authors: Hagel, M. / Miduturu, C. / Sheets, M. / Rubin, N. / Weng, W. / Stransky, N. / Bifulco, N. / Kim, J.L. / Hodous, B. / Brooijmans, N. / Shutes, A. / Winter, C. / Lengauer, C. / Kohl, N.E. / Guzi, T.
History
DepositionDec 18, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 2.0Dec 12, 2018Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / entity_src_gen / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_oper_list / pdbx_validate_close_contact / pdbx_validate_symm_contact / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _chem_comp.pdbx_synonyms / _entity.formula_weight / _entity.pdbx_description / _entity_src_gen.pdbx_alt_source_flag / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_struct_oper_list.symmetry_operation / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _pdbx_validate_symm_contact.auth_seq_id_1 / _pdbx_validate_symm_contact.auth_seq_id_2 / _struct_site_gen.auth_seq_id

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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)34,4753
Polymers33,8671
Non-polymers6072
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-9 kcal/mol
Surface area14290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.100, 58.110, 58.670
Angle α, β, γ (deg.)90.000, 94.420, 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: 33867.207 Da / Num. of mol.: 1 / Fragment: UNP residues 449-751 / Mutation: L449M, delta 570-578
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Spodoptera frugiperda (fall armyworm)
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-40M / N-(2-{[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino}-3-methylphenyl)propanamide / BLU9931 bound form


Mass: 511.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24Cl2N4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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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: 2.03 Å3/Da / Density % sol: 39.39 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 16% PEG 3350, 0.2M lithium sulfate, 0.1M bis-tris pH 4.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9394 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 30, 2012
RadiationMonochromator: channel cut ESRF monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9394 Å / Relative weight: 1
ReflectionResolution: 1.71→20 Å / Num. obs: 28521 / % possible obs: 99.5 % / Redundancy: 4.7 % / Net I/σ(I): 4.6
Reflection shellResolution: 1.71→1.8 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 1.7 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementResolution: 1.71→19.51 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.934 / SU B: 3.898 / SU ML: 0.121 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.129 / ESU R Free: 0.128 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2427 1400 4.9 %RANDOM
Rwork0.1931 27089 --
obs0.1956 27089 99.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 91.29 Å2 / Biso mean: 28.705 Å2 / Biso min: 10.16 Å2
Baniso -1Baniso -2Baniso -3
1-1.76 Å20 Å2-2.21 Å2
2---1.1 Å2-0 Å2
3----0.48 Å2
Refinement stepCycle: final / Resolution: 1.71→19.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2277 0 40 172 2489
Biso mean--26.71 36.4 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0192406
X-RAY DIFFRACTIONr_bond_other_d0.0010.022328
X-RAY DIFFRACTIONr_angle_refined_deg1.6721.9963270
X-RAY DIFFRACTIONr_angle_other_deg1.72535355
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1125293
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.81422.736106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.02115405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2551522
X-RAY DIFFRACTIONr_chiral_restr0.0930.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212669
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02546
LS refinement shellResolution: 1.705→1.749 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.416 116 -
Rwork0.37 1968 -
all-2084 -
obs--98.96 %

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