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

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Basic information

Entry
Database: PDB / ID: 4nks
TitleCrystal structure of human fibroblast growth factor receptor 1 kinase domain in complex with pyrazolaminopyrimidine 3
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 / 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 / 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 / positive regulation of cell cycle / peptidyl-tyrosine phosphorylation / 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-2M2 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 13, 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)71,0224
Polymers70,2712
Non-polymers7512
Water39622
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5112
Polymers35,1351
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5112
Polymers35,1351
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.058, 56.918, 66.242
Angle α, β, γ (deg.)90.00, 107.73, 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-2M2 / N~2~-[(3-methyl-1,2-oxazol-5-yl)methyl]-N~4~-[5-(2-phenylethyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine


Mass: 375.427 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H21N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.66 Å3/Da / Density % sol: 53.73 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.75
Details: 16-20% PEG 8000, 100mM PCTP, 100-300mM 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: ESRF / Beamline: ID14-4 / Wavelength: 0.976
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.5→99.01 Å / Num. all: 85026 / Num. obs: 23909 / % possible obs: 97.4 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 19.4
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.442 / Mean I/σ(I) obs: 3.8 / % possible all: 98.5

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Processing

Software
NameVersionClassification
AMoREphasing
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→99.01 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.9 / SU B: 20.039 / SU ML: 0.216 / Cross valid method: THROUGHOUT / ESU R: 0.433 / ESU R Free: 0.299 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27762 1286 5.1 %RANDOM
Rwork0.21958 ---
obs0.22251 23909 97.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 47.421 Å2
Baniso -1Baniso -2Baniso -3
1--4 Å20 Å2-2.58 Å2
2--5.95 Å2-0 Å2
3----0.93 Å2
Refinement stepCycle: LAST / Resolution: 2.5→99.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4113 0 56 22 4191
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0194262
X-RAY DIFFRACTIONr_bond_other_d0.0050.024015
X-RAY DIFFRACTIONr_angle_refined_deg1.461.9915778
X-RAY DIFFRACTIONr_angle_other_deg0.81439200
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9655526
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.40723.713167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.65515702
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3261526
X-RAY DIFFRACTIONr_chiral_restr0.0770.2654
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214713
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02905
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5753.8142134
X-RAY DIFFRACTIONr_mcbond_other2.5753.8132133
X-RAY DIFFRACTIONr_mcangle_it3.3275.7012647
X-RAY DIFFRACTIONr_mcangle_other3.3265.7022648
X-RAY DIFFRACTIONr_scbond_it2.9443.9492128
X-RAY DIFFRACTIONr_scbond_other2.9443.9482127
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.935.8573131
X-RAY DIFFRACTIONr_long_range_B_refined4.59430.394707
X-RAY DIFFRACTIONr_long_range_B_other4.59530.3644701
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.355 98 -
Rwork0.258 1732 -
obs--96.52 %
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)
11.6936-0.3226-0.22030.2923-0.2310.46480.06150.12560.1557-0.0059-0.0578-0.0432-0.08060.0574-0.00380.0696-0.0335-0.00620.04090.0360.060480.4431-2.309718.9745
22.4896-0.70970.32560.54560.23160.62960.21110.2757-0.1014-0.0001-0.17120.06560.07680.0103-0.03990.09950.007-0.02240.0631-0.01930.051333.84441.846513.8298
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A465 - 762
2X-RAY DIFFRACTION1A801
3X-RAY DIFFRACTION1A901 - 913
4X-RAY DIFFRACTION2B461 - 761
5X-RAY DIFFRACTION2B801
6X-RAY DIFFRACTION2B901 - 909

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