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- PDB-4qqc: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Domain in Compl... -

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Basic information

Entry
Database: PDB / ID: 4qqc
TitleCrystal Structure of FGF Receptor (FGFR) 4 Kinase Domain in Complex with FIIN-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate-Keeper Mutations
ComponentsFibroblast growth factor receptor 4
KeywordsTransferase/transferase inhibitor / Kinase Domain Fold / Cell Signaling / Phosphotransferase / Plasmamembrane / 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 / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / glucose homeostasis / PIP3 activates AKT signaling / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / 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-37O / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsHuang, Z. / Mohammadi, M.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2014
Title: Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
Authors: Tan, L. / Wang, J. / Tanizaki, J. / Huang, Z. / Aref, A.R. / Rusan, M. / Zhu, S.J. / Zhang, Y. / Ercan, D. / Liao, R.G. / Capelletti, M. / Zhou, W. / Hur, W. / Kim, N. / Sim, T. / Gaudet, S. ...Authors: Tan, L. / Wang, J. / Tanizaki, J. / Huang, Z. / Aref, A.R. / Rusan, M. / Zhu, S.J. / Zhang, Y. / Ercan, D. / Liao, R.G. / Capelletti, M. / Zhou, W. / Hur, W. / Kim, N. / Sim, T. / Gaudet, S. / Barbie, D.A. / Yeh, J.R. / Yun, C.H. / Hammerman, P.S. / Mohammadi, M. / Janne, P.A. / Gray, N.S.
History
DepositionJun 27, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 29, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)36,8923
Polymers36,1601
Non-polymers7332
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)139.830, 139.830, 49.486
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 36159.574 Da / Num. of mol.: 1 / Fragment: Kinase domain Of FGF Receptor 4 / Mutation: R669E
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-37O / N-(4-{[3-(3,5-dimethoxyphenyl)-7-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl]methyl}phenyl)propanamide


Mass: 636.743 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H40N8O4
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.57 Å3/Da / Density % sol: 52.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M HEPES, 1.0 1.2 M (NH4)2SO4, 10 mM Yttrium (III) chloride hexahydrate, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4C / Wavelength: 0.979 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Mar 14, 2014
RadiationMonochromator: Si 111 Channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. all: 15298 / Num. obs: 15298 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 11.3 % / Rmerge(I) obs: 0.106 / Rsym value: 0.106 / Net I/σ(I): 29.7
Reflection shellResolution: 2.35→2.39 Å / % possible all: 99.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8.4_1496)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2PSQ

2psq


Resolution: 2.4→27.79 Å / SU ML: 0.25 / σ(F): 2.04 / Phase error: 20.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.214 1417 10.04 %
Rwork0.1578 --
obs0.1633 14111 99.99 %
all-14111 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→27.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2132 0 52 41 2225
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082270
X-RAY DIFFRACTIONf_angle_d1.1423084
X-RAY DIFFRACTIONf_dihedral_angle_d16.954845
X-RAY DIFFRACTIONf_chiral_restr0.04336
X-RAY DIFFRACTIONf_plane_restr0.005394
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4001-2.48580.24731480.18931301X-RAY DIFFRACTION100
2.4858-2.58530.23741360.18041246X-RAY DIFFRACTION100
2.5853-2.70290.2411430.17431245X-RAY DIFFRACTION100
2.7029-2.84520.23471420.16491291X-RAY DIFFRACTION100
2.8452-3.02330.22231420.15951254X-RAY DIFFRACTION100
3.0233-3.25640.2171390.17541277X-RAY DIFFRACTION100
3.2564-3.58350.23051430.15761275X-RAY DIFFRACTION100
3.5835-4.10060.20851420.14611269X-RAY DIFFRACTION100
4.1006-5.16090.18531400.13371269X-RAY DIFFRACTION100
5.1609-27.79190.19521420.16131267X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -22.674 Å / Origin y: 3.6359 Å / Origin z: -9.834 Å
111213212223313233
T0.0621 Å20.0079 Å20.0153 Å2-0.1474 Å2-0.0121 Å2--0.1127 Å2
L0.4324 °2-0.0422 °20.3137 °2-0.2384 °2-0.3797 °2--0.4287 °2
S-0.0744 Å °-0.046 Å °-0.0466 Å °0.0234 Å °0.0642 Å °0.0248 Å °-0.0998 Å °-0.0944 Å °-0.0056 Å °
Refinement TLS groupSelection details: all

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