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

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Basic information

Entry
Database: PDB / ID: 7ozb
TitleFGFR1 kinase domain (residues 458-765) with mutations C488A, C584S in complex with 38.
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 / 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 / positive regulation of endothelial cell chemotaxis to fibroblast growth factor / 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 / FGFR1b ligand binding and activation / fibroblast growth factor receptor activity / 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 / phosphatidylinositol-mediated signaling / outer ear morphogenesis / middle ear morphogenesis / embryonic limb morphogenesis / skeletal system morphogenesis / ureteric bud development / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / positive regulation of vascular endothelial cell proliferation / inner ear morphogenesis / midbrain development / fibroblast growth factor binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / regulation of cell differentiation / PI-3K cascade:FGFR1 / PI3K Cascade / epithelial to mesenchymal transition / positive regulation of blood vessel endothelial cell migration / 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 / Signal transduction by L1 / skeletal system development / stem cell proliferation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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
Chem-47I / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 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 27, 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)71,99017
Polymers70,2712
Non-polymers1,72015
Water3,315184
1
AAA: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8857
Polymers35,1351
Non-polymers7506
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)36,10510
Polymers35,1351
Non-polymers9709
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)206.260, 57.560, 65.790
Angle α, β, γ (deg.)90.000, 107.220, 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: 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 BL21(DE3) (bacteria)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-47I / 4-[3-(4-piperazin-4-ium-1-ylphenyl)-1H-indazol-6-yl]phenol / 4-[3-(4-piperazin-1-ylphenyl)-1H-indazol-6-yl]phenol (uncharged compound's name)


Mass: 371.455 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.65 Å3/Da / Density % sol: 53.66 %
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: 1.71→98.51 Å / Num. obs: 77609 / % possible obs: 97.4 % / Redundancy: 3.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.042 / Rpim(I) all: 0.026 / Rrim(I) all: 0.049 / Net I/σ(I): 14.1
Reflection shellResolution: 1.71→1.75 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.969 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 5672 / CC1/2: 0.707 / Rpim(I) all: 0.737 / % possible all: 96.8

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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: 1.71→98.507 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.945 / SU B: 3.35 / SU ML: 0.102 / Cross valid method: FREE R-VALUE / ESU R: 0.109 / ESU R Free: 0.11
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2442 3823 4.926 %
Rwork0.2088 73786 -
all0.211 --
obs-77609 97.159 %
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: 39.414 Å2
Baniso -1Baniso -2Baniso -3
1--1.737 Å20 Å2-1.578 Å2
2--3.631 Å20 Å2
3----0.768 Å2
Refinement stepCycle: LAST / Resolution: 1.71→98.507 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4516 0 113 184 4813
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134755
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174449
X-RAY DIFFRACTIONr_angle_refined_deg1.3831.6656440
X-RAY DIFFRACTIONr_angle_other_deg1.2961.59110305
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2375584
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.55422.257226
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.15215818
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9791530
X-RAY DIFFRACTIONr_chiral_restr0.0640.2599
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025224
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02956
X-RAY DIFFRACTIONr_nbd_refined0.2070.2897
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1760.24132
X-RAY DIFFRACTIONr_nbtor_refined0.1620.22319
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0740.22005
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1520.2215
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2110.28
X-RAY DIFFRACTIONr_nbd_other0.1830.245
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0980.211
X-RAY DIFFRACTIONr_mcbond_it2.6234.0942333
X-RAY DIFFRACTIONr_mcbond_other2.6244.0912332
X-RAY DIFFRACTIONr_mcangle_it3.7576.1222915
X-RAY DIFFRACTIONr_mcangle_other3.7566.1252916
X-RAY DIFFRACTIONr_scbond_it3.14.4712422
X-RAY DIFFRACTIONr_scbond_other3.0944.4522415
X-RAY DIFFRACTIONr_scangle_it4.8126.5923524
X-RAY DIFFRACTIONr_scangle_other4.8126.5633513
X-RAY DIFFRACTIONr_lrange_it7.05947.4345555
X-RAY DIFFRACTIONr_lrange_other7.05847.4345556
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.71-1.7540.3532990.3545373X-RAY DIFFRACTION96.6105
1.754-1.8020.352980.3255217X-RAY DIFFRACTION96.6526
1.802-1.8550.3062810.2875123X-RAY DIFFRACTION96.8285
1.855-1.9120.2912680.2784982X-RAY DIFFRACTION97.0425
1.912-1.9740.2912530.2694859X-RAY DIFFRACTION97.3529
1.974-2.0440.2741820.2474743X-RAY DIFFRACTION97.3128
2.044-2.1210.2782470.2294543X-RAY DIFFRACTION97.2391
2.121-2.2070.2492140.2234388X-RAY DIFFRACTION97.6034
2.207-2.3050.2582140.2134201X-RAY DIFFRACTION97.4829
2.305-2.4180.2342270.2083986X-RAY DIFFRACTION97.5457
2.418-2.5490.281830.2133852X-RAY DIFFRACTION97.7945
2.549-2.7030.2511910.2053614X-RAY DIFFRACTION97.5141
2.703-2.890.2461830.2123404X-RAY DIFFRACTION97.2878
2.89-3.1210.2511740.2063146X-RAY DIFFRACTION96.793
3.121-3.4180.2281300.2062920X-RAY DIFFRACTION96.8869
3.418-3.8210.2261300.2012655X-RAY DIFFRACTION97.1399
3.821-4.4110.1961110.1712351X-RAY DIFFRACTION97.1203
4.411-5.40.2171040.1821994X-RAY DIFFRACTION97.4002
5.4-7.6260.314970.2261540X-RAY DIFFRACTION97.209
7.626-98.5070.184370.189895X-RAY DIFFRACTION95.4918

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