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

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Basic information

Entry
Database: PDB / ID: 7ozd
TitleFGFR1 kinase domain (residues 458-765) with mutations C488A, C584S in complex with 34.
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 / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / diphosphate metabolic process / ventricular zone neuroblast division / vitamin D3 metabolic process / regulation of phosphate transport ...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 / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / diphosphate metabolic process / ventricular zone neuroblast division / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / 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 / Epithelial-Mesenchymal Transition (EMT) during gastrulation / chordate embryonic development / positive regulation of parathyroid hormone secretion / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / positive regulation of phospholipase activity / mesenchymal cell proliferation / paraxial mesoderm development / lung-associated mesenchyme development / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / organ induction / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / cell projection assembly / cellular response to fibroblast growth factor stimulus / skeletal system morphogenesis / outer ear morphogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / embryonic limb morphogenesis / inner ear morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / midbrain development / cardiac muscle cell proliferation / fibroblast growth factor binding / regulation of cell differentiation / positive regulation of stem cell proliferation / PI-3K cascade:FGFR1 / Formation of paraxial mesoderm / phosphatidylinositol-mediated signaling / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / 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 / positive regulation of MAP kinase activity / neuron migration / receptor protein-tyrosine kinase / positive regulation of neuron projection development / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / neuron projection development / cell migration / PIP3 activates AKT signaling / heparin binding / gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / in utero embryonic development / protein autophosphorylation / positive regulation of MAPK cascade / 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 / extracellular region
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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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-(4-hydroxyphenyl)-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 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)72,00817
Polymers70,2712
Non-polymers1,73815
Water3,621201
1
AAA: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,13110
Polymers35,1351
Non-polymers9969
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)35,8777
Polymers35,1351
Non-polymers7426
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)207.300, 57.510, 65.970
Angle α, β, γ (deg.)90.000, 107.440, 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-42I / N-[6-(4-hydroxyphenyl)-1H-indazol-3-yl]benzamide


Mass: 329.352 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H15N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.67 Å3/Da / Density % sol: 53.92 %
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→22.01 Å / Num. obs: 66115 / % possible obs: 99.2 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.03 / Rpim(I) all: 0.024 / Rrim(I) all: 0.035 / Net I/σ(I): 16.7
Reflection shellResolution: 1.82→1.87 Å / Rmerge(I) obs: 0.836 / Num. unique obs: 4910 / CC1/2: 0.688 / Rpim(I) all: 0.598 / Rrim(I) all: 1.033

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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→22.01 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.95 / SU B: 3.861 / SU ML: 0.11 / Cross valid method: FREE R-VALUE / ESU R: 0.122 / ESU R Free: 0.123
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2412 3148 4.762 %
Rwork0.1995 62965 -
all0.201 --
obs-66113 99.074 %
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: 44.319 Å2
Baniso -1Baniso -2Baniso -3
1--1.327 Å20 Å2-1.948 Å2
2--4.434 Å20 Å2
3----1.573 Å2
Refinement stepCycle: LAST / Resolution: 1.82→22.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4419 0 110 201 4730
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134632
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174324
X-RAY DIFFRACTIONr_angle_refined_deg1.4391.6616273
X-RAY DIFFRACTIONr_angle_other_deg1.2691.58610016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3365566
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.9122.35217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.14615797
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3311528
X-RAY DIFFRACTIONr_chiral_restr0.0640.2580
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025075
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02935
X-RAY DIFFRACTIONr_nbd_refined0.2030.2869
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1760.23880
X-RAY DIFFRACTIONr_nbtor_refined0.1610.22241
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21936
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1380.2210
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.020.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1640.28
X-RAY DIFFRACTIONr_nbd_other0.1620.241
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1080.211
X-RAY DIFFRACTIONr_mcbond_it2.9574.5622273
X-RAY DIFFRACTIONr_mcbond_other2.9584.5612272
X-RAY DIFFRACTIONr_mcangle_it4.0846.8182833
X-RAY DIFFRACTIONr_mcangle_other4.0836.822834
X-RAY DIFFRACTIONr_scbond_it3.695.0442359
X-RAY DIFFRACTIONr_scbond_other3.695.0432360
X-RAY DIFFRACTIONr_scangle_it5.5667.4283439
X-RAY DIFFRACTIONr_scangle_other5.5667.4273440
X-RAY DIFFRACTIONr_lrange_it8.06453.285118
X-RAY DIFFRACTIONr_lrange_other8.06353.2785119
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
1.82-1.8670.3292170.35546540.35448900.3680.34599.61150.351
1.867-1.9180.3252220.3345000.32947380.5610.60199.66230.317
1.918-1.9730.3422310.2943820.29346210.7120.73599.82690.275
1.973-2.0330.292400.25142270.25344770.8120.84199.77660.232
2.033-2.0990.2661980.24341430.24443550.8770.87699.67850.225
2.099-2.1720.2431730.21240210.21442050.9110.91699.73840.193
2.172-2.2530.2622130.20938670.21140850.9020.91999.87760.192
2.253-2.3440.2651910.19737080.20139040.9120.93199.87190.181
2.344-2.4470.2461770.19636000.19837890.920.93599.68330.181
2.447-2.5650.2461630.19534300.19836040.9260.93899.69480.185
2.565-2.7020.2341670.19832420.234260.9170.93499.50380.191
2.702-2.8630.2781680.20930910.21332820.9040.9399.29920.207
2.863-3.0570.2071470.20328500.20330440.940.93798.4560.206
3.057-3.2970.2921300.20726940.21128750.890.92898.22610.217
3.297-3.6030.2361400.19524360.19726500.9260.94697.20760.21
3.603-4.0150.2241060.19221980.19323900.9360.94896.40170.213
4.015-4.6110.208850.15619930.15721350.9580.97197.33020.182
4.611-5.5860.204820.18116990.18218330.9620.96397.16310.218
5.586-7.6570.236680.21613510.21714540.9550.95497.59280.256
7.657-22.010.232300.1858790.1869310.9660.96597.63690.234

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