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- PDB-4qq5: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V... -

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Basic information

Entry
Database: PDB / ID: 4qq5
TitleCrystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation 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 / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 ...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 / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 / fibroblast growth factor binding / 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 / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / glucose homeostasis / cell migration / PIP3 activates AKT signaling / heparin binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / receptor complex / positive regulation of ERK1 and ERK2 cascade / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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: 2.203 Å
AuthorsHuang, Z. / Mohammadi, M.
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: DFG-out Mode of Inhibition by an Irreversible Type-1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors.
Authors: Huang, Z. / Tan, L. / Wang, H. / Liu, Y. / Blais, S. / Deng, J. / Neubert, T.A. / Gray, N.S. / Li, X. / Mohammadi, M.
History
DepositionJun 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 29, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)36,8102
Polymers36,1741
Non-polymers6371
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Fibroblast growth factor receptor 4
hetero molecules

A: Fibroblast growth factor receptor 4
hetero molecules

A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,4316
Polymers108,5213
Non-polymers1,9103
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_675-y+1,x-y+2,z1
crystal symmetry operation3_465-x+y-1,-x+1,z1
Buried area2220 Å2
ΔGint-25 kcal/mol
Surface area39650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.599, 139.599, 49.660
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: 36173.598 Da / Num. of mol.: 1 / Fragment: Kinase domain of FGF Receptor 4 / Mutation: R669E, V550L
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
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: 2.57 Å3/Da / Density % sol: 52.22 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M HEPES, 1.0 to 1.2 M (NH4)2SO4, and 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: 0.97947 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 11, 2014
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97947 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 18138 / Num. obs: 18138 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.9 % / Rmerge(I) obs: 0.102 / Rsym value: 0.102 / Net I/σ(I): 13.5
Reflection shellResolution: 2.2→2.24 Å / % possible all: 90.1

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Processing

Software
NameVersionClassification
HKL-3000data collection
PHENIXmodel building
PHENIX(phenix.refine: 1.8.4_1496)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2PSQ

2psq


Resolution: 2.203→38.372 Å / SU ML: 0.24 / σ(F): 1.98 / Phase error: 24.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2338 1812 9.99 %Random
Rwork0.193 ---
obs0.1972 18134 99.11 %-
all-18134 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.203→38.372 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2143 0 47 0 2190
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082241
X-RAY DIFFRACTIONf_angle_d1.2293044
X-RAY DIFFRACTIONf_dihedral_angle_d17.984836
X-RAY DIFFRACTIONf_chiral_restr0.042334
X-RAY DIFFRACTIONf_plane_restr0.007389
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2025-2.26210.24321290.2091188X-RAY DIFFRACTION91
2.2621-2.32860.26451400.2291236X-RAY DIFFRACTION98
2.3286-2.40380.26381390.22151269X-RAY DIFFRACTION100
2.4038-2.48970.28931440.21641278X-RAY DIFFRACTION100
2.4897-2.58930.30111390.2271252X-RAY DIFFRACTION100
2.5893-2.70710.26991360.2111236X-RAY DIFFRACTION100
2.7071-2.84980.27851430.22571277X-RAY DIFFRACTION100
2.8498-3.02830.23451420.211264X-RAY DIFFRACTION100
3.0283-3.2620.27611380.21781266X-RAY DIFFRACTION100
3.262-3.59010.23151390.19431277X-RAY DIFFRACTION100
3.5901-4.1090.20351390.16711263X-RAY DIFFRACTION100
4.109-5.17490.18581430.15551257X-RAY DIFFRACTION100
5.1749-38.37750.20711410.17611259X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -61.492 Å / Origin y: 142.256 Å / Origin z: 11.1489 Å
111213212223313233
T0.1892 Å2-0.0232 Å2-0.0017 Å2-0.128 Å20.0121 Å2--0.1622 Å2
L0.212 °20.1099 °20.0491 °2-0.414 °20.3206 °2--0.2598 °2
S0.0271 Å °-0.0244 Å °-0.0147 Å °-0.0892 Å °0.0002 Å °-0.0082 Å °-0.1023 Å °-0.0198 Å °0.0002 Å °
Refinement TLS groupSelection details: all

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