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- PDB-4zsa: Crystal structure of FGFR1 kinase domain in complex with 7n -

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Basic information

Entry
Database: PDB / ID: 4zsa
TitleCrystal structure of FGFR1 kinase domain in complex with 7n
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FGFR1 inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process ...Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / cementum mineralization / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / response to sodium phosphate / auditory receptor cell development / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / chordate embryonic development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / regulation of postsynaptic density assembly / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / skeletal system morphogenesis / positive regulation of mesenchymal cell proliferation / middle ear morphogenesis / ureteric bud development / cardiac muscle cell proliferation / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / midbrain development / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / fibroblast growth factor binding / regulation of cell differentiation / PI3K Cascade / cellular response to fibroblast growth factor stimulus / positive regulation of blood vessel endothelial cell migration / fibroblast growth factor receptor signaling pathway / epithelial to mesenchymal transition / chondrocyte differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / positive regulation of MAP kinase activity / positive regulation of neuron differentiation / SH2 domain binding / Signal transduction by L1 / stem cell proliferation / skeletal system development / positive regulation of cell differentiation / stem cell differentiation / sensory perception of sound / Negative regulation of FGFR1 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 / positive regulation of neuron projection development / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding
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 / 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 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / 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-4UT / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsLiu, Q.F. / Xu, Y.C.
CitationJournal: Org.Biomol.Chem. / Year: 2015
Title: Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.
Authors: Liu, J. / Peng, X. / Dai, Y. / Zhang, W. / Ren, S. / Ai, J. / Geng, M. / Li, Y.
History
DepositionMay 13, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 17, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2015Group: Database references
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_prerelease_seq / pdbx_struct_assembly / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation

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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)71,0684
Polymers70,1572
Non-polymers9112
Water4,792266
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5342
Polymers35,0781
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5342
Polymers35,0781
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)209.910, 57.181, 65.550
Angle α, β, γ (deg.)90.000, 107.470, 90.000
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 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35078.285 Da / Num. of mol.: 2 / Fragment: 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 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-4UT / 4-(4-ethylpiperazin-1-yl)-N-[6-(3-methoxyphenyl)-2H-indazol-3-yl]benzamide


Mass: 455.551 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H29N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / 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: 54.01 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M Bis-Tris pH 6.5, 0.3M (NH4)2SO4, 15-20% PEG10000, 5% EG

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 3, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionRedundancy: 3.7 % / Number: 187569 / Rmerge(I) obs: 0.055 / Χ2: 2.28 / D res high: 2 Å / D res low: 50 Å / Num. obs: 50138 / % possible obs: 99.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
5.435010.0282.8013.6
4.315.4310.032.1343.6
3.764.3110.0443.9653.7
3.423.7610.0636.3393.7
3.173.4210.0625.3233.7
2.993.1710.0613.3913.8
2.842.9910.062.4663.8
2.712.8410.0641.873.8
2.612.7110.0741.73.8
2.522.6110.0851.5843.8
2.442.5210.1061.5083.8
2.372.4410.1181.4833.8
2.312.3710.1421.4493.8
2.252.3110.181.463.8
2.22.2510.1991.4143.8
2.152.210.2411.4043.8
2.112.1510.2821.3513.8
2.072.1110.3561.3363.8
2.032.0710.4341.3453.8
22.0310.4861.3153.7
ReflectionResolution: 2→50 Å / Num. obs: 50138 / % possible obs: 99.5 % / Redundancy: 3.7 % / Biso Wilson estimate: 34.03 Å2 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.033 / Rrim(I) all: 0.065 / Χ2: 2.277 / Net I/av σ(I): 35.651 / Net I/σ(I): 15.4 / Num. measured all: 187569
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2-2.033.70.48624990.8960.290.5661.31599.8
2.03-2.073.80.43424960.9120.2570.5051.34599.8
2.07-2.113.80.35625140.940.2120.4151.33699.9
2.11-2.153.80.28224540.9650.1680.3281.35199.9
2.15-2.23.80.24125370.970.1440.2811.40499.9
2.2-2.253.80.19924730.9740.1190.2331.41499.9
2.25-2.313.80.1825200.9810.1070.211.46100
2.31-2.373.80.14224990.9880.0840.1651.44999.9
2.37-2.443.80.11824960.990.070.1381.48399.8
2.44-2.523.80.10624880.9920.0630.1241.50899.9
2.52-2.613.80.08525480.9950.0510.0991.584100
2.61-2.713.80.07425150.9950.0440.0871.799.9
2.71-2.843.80.06424920.9960.0380.0741.87100
2.84-2.993.80.0625300.9960.0360.072.46699.9
2.99-3.173.80.06125200.9950.0360.0713.391100
3.17-3.423.70.06225140.9940.0370.0735.32399.9
3.42-3.763.70.06325430.9920.0380.0736.33999.8
3.76-4.313.70.04425030.9970.0270.0523.96599.6
4.31-5.433.60.0325710.9980.0190.0362.13499.7
5.43-503.60.02824260.9980.0170.0332.80192.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHASER2.5.3phasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
Cootdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1AGW

1agw


Resolution: 2→34.366 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 0.15 / Phase error: 27.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2541 2004 4.22 %
Rwork0.2036 45523 -
obs0.2056 47527 94.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 93.08 Å2 / Biso mean: 42.8897 Å2 / Biso min: 20.27 Å2
Refinement stepCycle: final / Resolution: 2→34.366 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4514 0 68 266 4848
Biso mean--39.43 43.17 -
Num. residues----572
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084686
X-RAY DIFFRACTIONf_angle_d1.1436339
X-RAY DIFFRACTIONf_chiral_restr0.044687
X-RAY DIFFRACTIONf_plane_restr0.006809
X-RAY DIFFRACTIONf_dihedral_angle_d15.2221773
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.050.30381310.26072865299684
2.05-2.10540.32271290.25722949307887
2.1054-2.16730.2951360.24563078321490
2.1673-2.23730.29961320.2313092322490
2.2373-2.31720.29581420.22953188333093
2.3172-2.410.26041450.21823257340294
2.41-2.51960.30051410.22753265340696
2.5196-2.65240.28791430.22973345348897
2.6524-2.81850.27441540.22493361351598
2.8185-3.0360.25891520.23673380353299
3.036-3.34130.29311490.21733458360799
3.3413-3.82430.23461540.19243439359399
3.8243-4.81610.22371510.16393466361799
4.8161-34.3710.21571450.18183380352595

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