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- PDB-4uxq: FGFR4 in complex with Ponatinib -

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Basic information

Entry
Database: PDB / ID: 4uxq
TitleFGFR4 in complex with Ponatinib
ComponentsFIBROBLAST GROWTH FACTOR RECEPTOR 4
KeywordsTRANSFERASE / KINASE DFG-OUT FGFR 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-0LI / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.85 Å
AuthorsTucker, J. / Klein, T. / Breed, J. / Breeze, A. / Overman, R. / Phillips, C. / Norman, R.A.
CitationJournal: Structure / Year: 2014
Title: Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4
Authors: Tucker, J.A. / Klein, T. / Breed, J. / Breeze, A.L. / Overman, R. / Phillips, C. / Norman, R.A.
History
DepositionAug 27, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 10, 2014Group: Database references / Other
Revision 1.2Dec 17, 2014Group: Database references
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _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)35,0833
Polymers34,4551
Non-polymers6292
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.835, 58.371, 60.570
Angle α, β, γ (deg.)90.00, 96.48, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein FIBROBLAST GROWTH FACTOR RECEPTOR 4 / FGFR-4 / FGFR4 / CD334


Mass: 34454.723 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 447-753 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
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-0LI / 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide / Ponatinib


Mass: 532.559 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27F3N6O / Comment: medication*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2

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Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.86 % / Description: NONE
Crystal growDetails: 0.1MPCTP, PH4.5 0.1M (NH4)2SO4, 15% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.85→30 Å / Num. obs: 14141 / % possible obs: 57 % / Observed criterion σ(I): 1 / Redundancy: 4.6 % / Biso Wilson estimate: 14.98 Å2 / Rmerge(I) obs: 0.18 / Net I/σ(I): 7.3
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.287 / Mean I/σ(I) obs: 2.6 / % possible all: 8

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Processing

SoftwareName: BUSTER / Version: 2.11.5 / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.85→20 Å / Cor.coef. Fo:Fc: 0.9265 / Cor.coef. Fo:Fc free: 0.8525 / SU R Cruickshank DPI: 0.354 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.389 / SU Rfree Blow DPI: 0.256 / SU Rfree Cruickshank DPI: 0.252
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2681 714 5.07 %RANDOM
Rwork0.2014 ---
obs0.2048 14086 56.64 %-
Displacement parametersBiso mean: 23.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.8056 Å20 Å20.2099 Å2
2---0.1429 Å20 Å2
3---0.9485 Å2
Refine analyzeLuzzati coordinate error obs: 0.275 Å
Refinement stepCycle: LAST / Resolution: 1.85→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 44 228 2512
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012345HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.123189HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d790SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes349HARMONIC5
X-RAY DIFFRACTIONt_it2345HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion18.5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion283SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2884SEMIHARMONIC4
LS refinement shellResolution: 1.85→2 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2231 29 5.94 %
Rwork0.2043 459 -
all0.2055 488 -
obs--56.64 %
Refinement TLS params.Method: refined / Origin x: 3.7986 Å / Origin y: -0.8149 Å / Origin z: 15.4534 Å
111213212223313233
T0.0298 Å20.0129 Å2-0.0672 Å2--0.1569 Å2-0.0004 Å2---0.1793 Å2
L0.3294 °20.0671 °20.3292 °2-0.4166 °20.1629 °2--0.895 °2
S-0.005 Å °0.0177 Å °-0.0317 Å °-0.0053 Å °-0.0001 Å °-0.0079 Å °0.042 Å °0.0118 Å °0.0051 Å °
Refinement TLS groupSelection details: CHAIN A AND RESID 452-750

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