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- PDB-8yki: FGFR-1 in complex with ligand tasurgratinib -

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Basic information

Entry
Database: PDB / ID: 8yki
TitleFGFR-1 in complex with ligand tasurgratinib
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / FGF RECEPTOR KINASE / PROTEROS BIOSTRUCTURES GMBH
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 / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification ...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 / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / response to sodium phosphate / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of parathyroid hormone secretion / chordate embryonic development / mesenchymal cell proliferation / paraxial mesoderm development / fibroblast growth factor receptor activity / FGFR1b ligand binding and activation / branching involved in salivary gland morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / cellular response to fibroblast growth factor stimulus / outer ear morphogenesis / middle ear morphogenesis / skeletal system morphogenesis / embryonic limb morphogenesis / ureteric bud development / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / positive regulation of endothelial cell chemotaxis / midbrain development / inner ear morphogenesis / fibroblast growth factor binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / regulation of cell differentiation / phosphatidylinositol-mediated signaling / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / : / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / neuron migration / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / neuron projection development / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding / gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / RAF/MAP kinase cascade / protein tyrosine kinase activity / angiogenesis / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein phosphorylation / positive regulation of cell population proliferation / negative regulation of transcription by RNA polymerase II / protein homodimerization activity
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 / Tyrosine 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 / 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
Similarity search - Domain/homology
: / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsIkemori-Kawada, M. / Watanabe Miyano, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Anticancer Res. / Year: 2024
Title: Antitumor Activity of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor in Cholangiocarcinoma Models With FGFR2-fusion.
Authors: Kawano, S. / Kawada, M.I. / Fukushima, S. / Arai, Y. / Shibata, T. / Miyano, S.W.
History
DepositionMar 5, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release

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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)73,4796
Polymers72,2332
Non-polymers1,2464
Water18010
1
A: Fibroblast growth factor receptor 1
hetero molecules


  • defined by author&software
  • 36.7 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,7403
Polymers36,1161
Non-polymers6232
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-1 kcal/mol
Surface area14470 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


  • defined by author&software
  • 36.7 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,7403
Polymers36,1161
Non-polymers6232
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-2 kcal/mol
Surface area14100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)214.362, 50.260, 64.906
Angle α, β, γ (deg.)90.000, 107.000, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: THR / End label comp-ID: THR / Refine code: _ / Auth seq-ID: 464 - 761 / Label seq-ID: 7 - 304

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: 36116.473 Da / Num. of mol.: 2 / Mutation: C488A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Cell line (production host): Sf9 / Production host: Spodoptera (butterflies/moths)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1LY1 / Tasurgratinib / E-7090


Mass: 587.666 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H37N5O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.31 Å3/Da / Density % sol: 46.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 18% w/v PEG 3350, 0.2M (NH4)2 TARTRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99977 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99977 Å / Relative weight: 1
ReflectionResolution: 2.79→102.5 Å / Num. obs: 16388 / % possible obs: 97.5 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.046 / Net I/σ(I): 19.3
Reflection shellResolution: 2.79→3.04 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.446 / Num. unique obs: 3721 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.79→102.5 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.901 / SU B: 42.058 / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.417 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2879 680 4.1 %RANDOM
Rwork0.2403 ---
obs0.2421 15708 97.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 173.02 Å2 / Biso mean: 88.27 Å2 / Biso min: 31.65 Å2
Baniso -1Baniso -2Baniso -3
1--0.66 Å2-0 Å2-2.23 Å2
2--5.14 Å20 Å2
3----2.62 Å2
Refinement stepCycle: final / Resolution: 2.79→102.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4232 0 82 10 4324
Biso mean--83.57 57.8 -
Num. residues----533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194129
X-RAY DIFFRACTIONr_bond_other_d0.0020.023938
X-RAY DIFFRACTIONr_angle_refined_deg1.3661.9985607
X-RAY DIFFRACTIONr_angle_other_deg1.14638983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9165525
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.35223.673147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.73115.111674
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.8281522
X-RAY DIFFRACTIONr_chiral_restr0.070.2637
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214607
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02867
X-RAY DIFFRACTIONr_mcbond_it2.3725.372124
X-RAY DIFFRACTIONr_mcbond_other2.3725.3692123
X-RAY DIFFRACTIONr_mcangle_it3.8579.0422641
Refine LS restraints NCS

Ens-ID: 1 / Number: 14710 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.05 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.79→2.862 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 51 -
Rwork0.324 1131 -
all-1182 -
obs--98.99 %
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)
15.3683-0.54511.20893.9931-2.6236.88680.0637-0.1362-0.33260.0009-0.0318-0.06380.7930.1405-0.0320.12310.0318-0.00880.5286-0.00640.1705-6.609-43.17715.661
23.97370.1447-0.13060.5985-0.23917.1226-0.1054-0.1354-0.09330.00690.10620.4040.0307-0.5287-0.00090.00460.02790.00790.50550.050.3084-23.485-34.114-3.76
35.3379-2.16770.13686.3406-1.64276.560.0656-0.02110.42520.02050.1137-0.1412-0.3509-0.0763-0.17930.11760.0108-0.01860.56830.03740.2524-36.606-18.10736.797
48.6240.54461.56833.0004-0.0185.1486-0.12991.11390.2783-0.4838-0.13520.2596-0.40020.00210.2650.28620.13720.01680.97390.15850.4722-51.765-11.44614.924
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A464 - 563
2X-RAY DIFFRACTION2A564 - 762
3X-RAY DIFFRACTION3B459 - 563
4X-RAY DIFFRACTION4B564 - 761

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