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- PDB-4nka: Crystal structure of human fibroblast growth factor receptor 1 ki... -

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Basic information

Entry
Database: PDB / ID: 4nka
TitleCrystal structure of human fibroblast growth factor receptor 1 kinase domain in complex with pyrazolaminopyrimidine 2
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 / positive regulation of phospholipase activity / receptor-receptor interaction / regulation of postsynaptic density assembly / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade: FGFR1 / skeletal system morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / positive regulation of MAP kinase activity / fibroblast growth factor receptor signaling pathway / phosphatidylinositol-mediated signaling / regulation of cell differentiation / fibroblast growth factor binding / epithelial to mesenchymal transition / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / peptidyl-tyrosine phosphorylation / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / positive regulation of cell cycle / NCAM signaling for neurite out-growth / SH2 domain binding / Signal transduction by L1 / skeletal system development / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / receptor protein-tyrosine kinase / neuron migration / 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 / protein phosphorylation / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynapse / signaling receptor complex / positive regulation of cell population proliferation / glutamatergic synapse / negative regulation of transcription by RNA polymerase II / DNA-templated transcription / protein homodimerization activity / 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-2K7 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsNorman, R.A. / Klein, T.
CitationJournal: ACS Med Chem Lett / Year: 2014
Title: FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures.
Authors: Klein, T. / Tucker, J. / Holdgate, G.A. / Norman, R.A. / Breeze, A.L.
History
DepositionNov 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2014Group: 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)71,61610
Polymers70,2712
Non-polymers1,3458
Water3,891216
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)208.830, 57.360, 65.730
Angle α, β, γ (deg.)90.00, 107.68, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1015-

HOH

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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.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-2K7 / N~4~-{3-[2-(3,4-dimethoxyphenyl)ethyl]-1H-pyrazol-5-yl}-N~2~-[(3-methyl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine


Mass: 435.479 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H25N7O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 2.67 Å3/Da / Density % sol: 53.91 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.75
Details: 18-20% PEG 8000, 100mM PCTP, 200mM ammonium sulfate, 25% ethylene glycol, pH 6.75, VAPOR DIFFUSION, HANGING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.976
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 24, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.19→46.42 Å / Num. all: 119467 / Num. obs: 37902 / % possible obs: 98.6 % / Redundancy: 3.2 % / Biso Wilson estimate: 54.95 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 21.3
Reflection shellResolution: 2.19→2.25 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.446 / Mean I/σ(I) obs: 2.3 / % possible all: 95.7

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Processing

Software
NameVersionClassification
GDAdata collection
AMoREphasing
BUSTER2.11.5refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.19→46.42 Å / Cor.coef. Fo:Fc: 0.9493 / Cor.coef. Fo:Fc free: 0.9367 / SU R Cruickshank DPI: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2279 1894 5 %RANDOM
Rwork0.1982 ---
obs0.1997 37902 98.57 %-
Displacement parametersBiso mean: 68.38 Å2
Baniso -1Baniso -2Baniso -3
1-6.795 Å20 Å2-0.4775 Å2
2---14.3794 Å20 Å2
3---7.5844 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.19→46.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4338 0 91 216 4645
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014566HARMONIC2
X-RAY DIFFRACTIONt_angle_deg16231HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1532SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes107HARMONIC2
X-RAY DIFFRACTIONt_gen_planes650HARMONIC5
X-RAY DIFFRACTIONt_it4566HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion17.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion575SEMIHARMONIC5
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_contact5092SEMIHARMONIC4
LS refinement shellResolution: 2.19→2.25 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.252 143 5.06 %
Rwork0.2445 2683 -
all0.2449 2826 -
obs--98.57 %
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)
12.5451-0.4041-0.54230.38360.02251.22470.13470.18440.2689-0.1082-0.0516-0.0016-0.14810.0208-0.0831-0.3280.0371-0.01050.06160.0497-0.36780.591-2.512217.8126
23.5817-0.96330.13741.08270.40561.25790.19170.4628-0.3010.1679-0.28020.1230.15240.04940.0885-0.34780.0066-0.04040.0467-0.0196-0.377234.35331.578414.4177
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|464 - A|765 }A464 - 765
2X-RAY DIFFRACTION2{ B|458 - B|765 }B458 - 765

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