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- PDB-4f65: Crystal structure of Human Fibroblast Growth Factor Receptor 1 Ki... -

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Basic information

Entry
Database: PDB / ID: 4f65
TitleCrystal structure of Human Fibroblast Growth Factor Receptor 1 Kinase domain in complex with compound 8
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / ATP binding / phosphorylation / trans-membrane / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / Signaling by plasma membrane FGFR1 fusions / cementum mineralization / chordate embryonic development / response to sodium phosphate / Epithelial-Mesenchymal Transition (EMT) during gastrulation / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division ...Signaling by FGFR1 amplification mutants / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / Signaling by plasma membrane FGFR1 fusions / cementum mineralization / chordate embryonic development / response to sodium phosphate / Epithelial-Mesenchymal Transition (EMT) during gastrulation / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / receptor-receptor interaction / positive regulation of phospholipase activity / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / fibroblast growth factor receptor activity / skeletal system morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / fibroblast growth factor receptor signaling pathway / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / positive regulation of MAP kinase activity / regulation of cell differentiation / phosphatidylinositol-mediated signaling / fibroblast growth factor binding / epithelial to mesenchymal transition / PI3K Cascade / skeletal system development / positive regulation of blood vessel endothelial cell migration / positive regulation of neuron differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / peptidyl-tyrosine phosphorylation / positive regulation of cell cycle / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / Signal transduction by L1 / positive regulation of cell differentiation / neuron migration / Negative regulation of FGFR1 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / PIP3 activates AKT signaling / protein autophosphorylation / cell migration / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / cytoplasmic vesicle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / protein phosphorylation / signaling receptor complex / postsynapse / positive regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / glutamatergic synapse / protein homodimerization activity / DNA-templated transcription / extracellular region / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytosol
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-0S9 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsNorman, R.A. / Breed, J. / Ogg, D.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Protein-Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase.
Authors: Norman, R.A. / Schott, A.K. / Andrews, D.M. / Breed, J. / Foote, K.M. / Garner, A.P. / Ogg, D. / Orme, J.P. / Pink, J.H. / Roberts, K. / Rudge, D.A. / Thomas, A.P. / Leach, A.G.
History
DepositionMay 14, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_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

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,18418
Polymers70,2712
Non-polymers1,91416
Water3,423190
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)210.713, 50.365, 65.641
Angle α, β, γ (deg.)90.00, 106.67, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35135.340 Da / Num. of mol.: 2 / Fragment: kinase domain (UNP residues 458-765) / Mutation: C488A, C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-0S9 / 5-bromo-N~2~-[(3-methyl-1,2-oxazol-5-yl)methyl]-N~4~-[3-(2-phenylethyl)-1H-pyrazol-5-yl]pyrimidine-2,4-diamine


Mass: 454.323 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20BrN7O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 2.37 Å3/Da / Density % sol: 48.19 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 16-20% PEG8000, 100 mM PCTP, 100-300 mM ammonium sulfate, 25% ethylene glycol, pH 6.25-7.25, VAPOR DIFFUSION, HANGING DROP, temperature 277K
PH range: 6.25-7.25

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Feb 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.259→100.929 Å / Num. all: 31333 / Num. obs: 30388 / % possible obs: 96.23 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.3 % / Biso Wilson estimate: 45.47 Å2 / Rmerge(I) obs: 0.041 / Rsym value: 0.027 / Net I/σ(I): 21.3
Reflection shellResolution: 2.259→2.38 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.27 / Mean I/σ(I) obs: 4.7 / Rsym value: 0.213 / % possible all: 80.17

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→39.95 Å / Cor.coef. Fo:Fc: 0.9332 / Cor.coef. Fo:Fc free: 0.9237 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.298 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.299 / SU Rfree Blow DPI: 0.211 / SU Rfree Cruickshank DPI: 0.212
RfactorNum. reflection% reflectionSelection details
Rfree0.2355 1504 5.02 %RANDOM
Rwork0.2026 ---
obs0.2043 29937 95.72 %-
Displacement parametersBiso max: 159.86 Å2 / Biso mean: 49.6558 Å2 / Biso min: 20.8 Å2
Baniso -1Baniso -2Baniso -3
1-7.8011 Å20 Å20.5187 Å2
2---10.9732 Å20 Å2
3---3.1721 Å2
Refinement stepCycle: LAST / Resolution: 2.26→39.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4354 0 118 190 4662
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1579SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes99HARMONIC2
X-RAY DIFFRACTIONt_gen_planes664HARMONIC5
X-RAY DIFFRACTIONt_it4560HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion572SEMIHARMONIC5
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_contact5260SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4560HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6152HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.98
X-RAY DIFFRACTIONt_other_torsion17.43
LS refinement shellResolution: 2.26→2.34 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2566 105 4.56 %
Rwork0.2252 2197 -
all0.2266 2302 -
obs--95.72 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5325-0.06290.560.70190.10932.19790.08250.0114-0.01280.0077-0.124-0.06250.2579-0.03450.0415-0.09010.01960.0158-0.05490.0031-0.157518.31250.9367-2.3017
22.1138-0.24171.09030.8154-0.53812.0037-0.0529-0.1886-0.00050.08240.05940.133-0.08660.0304-0.0065-0.08990.01090.0069-0.1302-0.0037-0.079659.4439-0.906422.6107
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A464 - 765
2X-RAY DIFFRACTION2{ B|* }B460 - 763

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