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- PDB-7ozf: FGFR1 kinase domain (residues 458-765) with mutations C488A, C584... -

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Basic information

Entry
Database: PDB / ID: 7ozf
TitleFGFR1 kinase domain (residues 458-765) with mutations C488A, C584S in complex with 19.
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / FGFR1 / Inhibitor / receptor tyrosine kinase
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 / vitamin D3 metabolic process / cementum mineralization / 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 / positive regulation of parathyroid hormone secretion / auditory receptor cell development / 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 / 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
N-[6-(3-ethoxyphenyl)-1H-indazol-3-yl]benzamide / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsTrinh, C.H. / Turner, L.D. / Fishwick, C.W.G.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/K501402/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.
Authors: Turner, L.D. / Trinh, C.H. / Hubball, R.A. / Orritt, K.M. / Lin, C.C. / Burns, J.E. / Knowles, M.A. / Fishwick, C.W.G.
History
DepositionJun 28, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Fibroblast growth factor receptor 1
BBB: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,40111
Polymers70,2712
Non-polymers1,1309
Water3,297183
1
AAA: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7486
Polymers35,1351
Non-polymers6135
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
BBB: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6525
Polymers35,1351
Non-polymers5174
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.320, 57.770, 65.940
Angle α, β, γ (deg.)90.000, 107.170, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AAABBB

#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: 35135.340 Da / Num. of mol.: 2 / Fragment: UNP residues 458-765
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

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Non-polymers , 5 types, 192 molecules

#2: Chemical ChemComp-466 / N-[6-(3-ethoxyphenyl)-1H-indazol-3-yl]benzamide


Mass: 357.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 183 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.7 Å3/Da / Density % sol: 54.4 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.7
Details: 0.185M ammonium sulfate, 20% v/v ethylene glycol, 17% w/v PEG 8000, 0.1M PCPT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.82→63 Å / Num. obs: 225749 / % possible obs: 98.7 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.026 / Rrim(I) all: 0.05 / Net I/σ(I): 11.3
Reflection shellResolution: 1.82→1.87 Å / Rmerge(I) obs: 0.871 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4933 / CC1/2: 0.625 / Rpim(I) all: 0.609 / Rrim(I) all: 1.067

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Processing

Software
NameVersionClassification
xia2data reduction
Aimless0.5.32data scaling
PHASERphasing
REFMAC5.8.0258refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5A4C

5a4c


Resolution: 1.82→63 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.951 / SU B: 4.266 / SU ML: 0.121 / Cross valid method: FREE R-VALUE / ESU R: 0.125 / ESU R Free: 0.124
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2425 3411 5.13 %
Rwork0.204 63079 -
all0.206 --
obs-66490 98.673 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 46.193 Å2
Baniso -1Baniso -2Baniso -3
1--1.947 Å20 Å2-0.808 Å2
2--3.919 Å20 Å2
3----1.236 Å2
Refinement stepCycle: LAST / Resolution: 1.82→63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4421 0 77 183 4681
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134658
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174352
X-RAY DIFFRACTIONr_angle_refined_deg1.4471.6626307
X-RAY DIFFRACTIONr_angle_other_deg1.2531.58910064
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2285576
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.60222.136220
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.17415787
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7241529
X-RAY DIFFRACTIONr_chiral_restr0.0620.2586
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025171
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02962
X-RAY DIFFRACTIONr_nbd_refined0.1950.2836
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1720.23900
X-RAY DIFFRACTIONr_nbtor_refined0.1580.22276
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21955
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2166
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1570.28
X-RAY DIFFRACTIONr_nbd_other0.1730.241
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.150.26
X-RAY DIFFRACTIONr_mcbond_it3.0644.8382316
X-RAY DIFFRACTIONr_mcbond_other3.0644.8362315
X-RAY DIFFRACTIONr_mcangle_it4.3397.2322888
X-RAY DIFFRACTIONr_mcangle_other4.3397.2342889
X-RAY DIFFRACTIONr_scbond_it3.5745.1742342
X-RAY DIFFRACTIONr_scbond_other3.5745.1742343
X-RAY DIFFRACTIONr_scangle_it5.5277.6253419
X-RAY DIFFRACTIONr_scangle_other5.5267.6253420
X-RAY DIFFRACTIONr_lrange_it7.14555.1165082
X-RAY DIFFRACTIONr_lrange_other7.13955.065067
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.82-1.8670.3672620.36746690.36749410.4710.49499.79760.366
1.867-1.9180.3622460.34145440.34247960.520.56799.87490.335
1.918-1.9740.3492380.30644310.30846780.660.66799.80760.298
1.974-2.0350.32380.2743180.27245590.7940.79899.93420.257
2.035-2.1010.2912470.25541720.25744210.8460.84899.95480.243
2.101-2.1750.2672260.22640750.22843030.8820.89999.95350.213
2.175-2.2570.2582300.22639030.22841330.8880.8991000.215
2.257-2.3490.2552120.20637540.20839720.920.92999.84890.197
2.349-2.4530.2491690.19836500.238310.920.93499.68680.191
2.453-2.5730.2481810.21334780.21536710.9030.92199.67310.21
2.573-2.7120.2711710.21532640.21834550.8980.92399.42110.216
2.712-2.8760.2691570.2130950.21333050.9070.92998.39640.216
2.876-3.0740.2731470.2228890.22331040.8920.91397.80930.233
3.074-3.320.2531490.21126290.21428870.9150.92696.22450.229
3.32-3.6360.2511130.19224350.19526930.9290.95394.61570.213
3.636-4.0630.2041030.18421570.18524010.9520.95294.12740.211
4.063-4.6880.1871120.15119350.15321460.960.96995.38680.183
4.688-5.7340.233990.17916250.18218270.9440.9694.36230.223
5.734-8.0760.25760.2112790.21314240.9310.9595.15450.257
8.076-63.0010.188350.217770.2098360.9560.9597.12920.285

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