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- PDB-5z0s: Crystal structure of FGFR1 kinase domain in complex with a novel ... -

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Basic information

Entry
Database: PDB / ID: 5z0s
TitleCrystal structure of FGFR1 kinase domain in complex with a novel inhibitor
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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / vitamin D3 metabolic process / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / receptor-receptor interaction / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / chordate embryonic development / auditory receptor cell development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / sensory perception of sound / positive regulation of neuron projection development / receptor protein-tyrosine kinase / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / postsynapse / positive regulation of MAPK cascade / positive regulation of cell population proliferation / glutamatergic synapse
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 / 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-960 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.45 Å
AuthorsLiu, Q. / Xu, Y.
CitationJournal: Molecules / Year: 2018
Title: Structure-Based Discovery of a Series of 5H-Pyrrolo[2,3-b]pyrazine FGFR Kinase Inhibitors
Authors: Jiang, A. / Liu, Q. / Wang, R. / Wei, P. / Dai, Y. / Wang, X. / Xu, Y. / Ma, Y. / Ai, J. / Shen, J. / Ding, J. / Xiong, B.
History
DepositionDec 20, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 26, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)70,9864
Polymers70,1572
Non-polymers8302
Water1,02757
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4932
Polymers35,0781
Non-polymers4151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4932
Polymers35,0781
Non-polymers4151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)210.130, 57.980, 65.360
Angle α, β, γ (deg.)90.000, 107.380, 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 / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-960 / 1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)sulfonyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-b]pyridine


Mass: 414.829 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H11ClN8O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / 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: 2.71 Å3/Da / Density % sol: 54.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting 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: BL17U1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.45→43.799 Å / Num. obs: 49913 / % possible obs: 92.1 % / Redundancy: 1.918 % / Biso Wilson estimate: 35.8 Å2 / CC1/2: 0.977 / Rmerge(I) obs: 0.104 / Rrim(I) all: 0.143 / Χ2: 1.159 / Net I/σ(I): 6.11 / Num. measured all: 95745 / Scaling rejects: 123
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.45-2.511.9540.4462.367637407039090.7740.60696
2.51-2.581.950.4862.56886385335310.6830.6691.6
2.58-2.661.8460.3352.584963380926880.9170.46470.6
2.66-2.741.8920.382.935301372128020.8730.52475.3
2.74-2.831.9460.2663.896409353832940.8980.36293.1
2.83-2.931.9430.1684.86442345033160.9490.22996.1
2.93-3.041.9360.1445.46364339632870.960.19796.8
3.04-3.161.920.1136.095913316330790.9770.15597.3
3.16-3.31.9130.0996.915727309729930.9750.13696.6
3.3-3.461.90.0917.25410293028470.9790.12597.2
3.46-3.651.8860.0857.675218285627660.9780.11896.8
3.65-3.871.8520.0858.174605262224870.9710.11794.9
3.87-4.141.9670.0768.964652251223650.9760.10694.1
4.14-4.471.9670.0749.614256229221640.9760.10294.4
4.47-4.91.9610.0749.73944212920110.9740.10394.5
4.9-5.481.9350.0739.73610194618660.9740.195.9
5.48-6.331.9140.0729.533102167316210.9740.10196.9
6.33-7.751.8940.0729.752589143813670.970.10195.1
7.75-10.961.8340.07110.261885113110280.9670.190.9
10.96-43.7991.6910.0759.838325914920.9620.10683.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZSA

4zsa


Resolution: 2.45→43.799 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 0.86 / Phase error: 32.58 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2747 1492 3 %
Rwork0.2252 48228 -
obs0.2266 49720 91.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.44 Å2 / Biso mean: 41.6378 Å2 / Biso min: 17.51 Å2
Refinement stepCycle: final / Resolution: 2.45→43.799 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4435 0 56 57 4548
Biso mean--51.9 38.14 -
Num. residues----566
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094599
X-RAY DIFFRACTIONf_angle_d1.0186233
X-RAY DIFFRACTIONf_chiral_restr0.052687
X-RAY DIFFRACTIONf_plane_restr0.007787
X-RAY DIFFRACTIONf_dihedral_angle_d5.2233891
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4501-2.52910.39031470.28014616476396
2.5291-2.61950.37511280.33644105423387
2.6195-2.72440.4316940.4153138323265
2.7244-2.84840.36061350.28454388452392
2.8484-2.99850.33691430.26824575471897
2.9985-3.18630.29611450.25584631477697
3.1863-3.43220.27391450.23224657480297
3.4322-3.77750.31591380.21224609474797
3.7775-4.32370.24041390.18814470460994
4.3237-5.44570.22391420.1734578472095
5.4457-43.80620.1891360.19474461459794

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