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- PDB-5b7v: Human FGFR1 kinase in complex with CH5183284 -

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Basic information

Entry
Database: PDB / ID: 5b7v
TitleHuman FGFR1 kinase in complex with CH5183284
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / ATP-binding / 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 / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation ...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 / 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 / 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 / chordate embryonic development / positive regulation of parathyroid hormone secretion / 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 / organ induction / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / positive regulation of phospholipase activity / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / cellular response to fibroblast growth factor stimulus / outer ear morphogenesis / middle ear morphogenesis / embryonic limb morphogenesis / skeletal system morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / positive regulation of endothelial cell chemotaxis / ureteric bud development / cardiac muscle cell proliferation / inner ear morphogenesis / midbrain development / regulation of cell differentiation / positive regulation of stem cell proliferation / PI-3K cascade:FGFR1 / fibroblast growth factor binding / Formation of paraxial mesoderm / phosphatidylinositol-mediated signaling / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / chondrocyte differentiation / calcium ion homeostasis / 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 / 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-LWJ / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.15 Å
AuthorsFukami, T.A. / Lukacs, C.M. / Janson, C.
CitationJournal: Mol.Cancer Ther. / Year: 2014
Title: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor
Authors: Nakanishi, Y. / Akiyama, N. / Tsukaguchi, T. / Fujii, T. / Sakata, K. / Sase, H. / Isobe, T. / Morikami, K. / Shindoh, H. / Mio, T. / Ebiike, H. / Taka, N. / Aoki, Y. / Ishii, N.
History
DepositionJun 9, 2016Deposition site: PDBJ / Processing site: PDBJ
SupersessionJun 22, 2016ID: 3WJ6
Revision 1.0Jun 22, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_prerelease_seq / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)71,4265
Polymers70,6172
Non-polymers8093
Water1,35175
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7613
Polymers35,3091
Non-polymers4522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-10 kcal/mol
Surface area14580 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6652
Polymers35,3091
Non-polymers3561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)211.210, 56.750, 65.450
Angle α, β, γ (deg.)90.000, 107.430, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Fibroblast growth factor receptor 1


Mass: 35308.613 Da / Num. of mol.: 2 / Fragment: tyrosine kinase domain, UNP residues 456-765 / Mutation: L457V, C488A, C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-LWJ / [5-amino-1-(2-methyl-1H-benzimidazol-6-yl)-1H-pyrazol-4-yl](1H-indol-2-yl)methanone


Mass: 356.381 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16N6O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 75 / 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: 2.7 Å3/Da / Density % sol: 53.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: PEG 10000, (NH4)2SO4, BIS-TRIS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 12, 2011 / Details: mirrors
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→43.351 Å / Num. all: 48444 / Num. obs: 48444 / % possible obs: 99.3 % / Redundancy: 3.4 % / Rpim(I) all: 0.024 / Rrim(I) all: 0.044 / Rsym value: 0.033 / Net I/av σ(I): 13.714 / Net I/σ(I): 14.9 / Num. measured all: 163718
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.02-2.133.30.6961.1199.1
2.13-2.263.50.3831.8198.9
2.26-2.413.50.2063.6199.5
2.41-2.613.30.1246199.5
2.61-2.863.50.0739.9199.5
2.86-3.193.40.04316.4199.5
3.19-3.693.30.02921.9199.3
3.69-4.523.40.02228.7199.4
4.52-6.393.20.0231.6199.1
6.39-43.3513.20.01827.8198.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata processing
SCALA3.3.18data processing
PDB_EXTRACT3.1data extraction
BUSTER2.11.7refinement
HKLdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1GAG

1gag


Resolution: 2.15→31.24 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.893 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.256 1983 5.04 %RANDOM
Rwork0.223 ---
obs0.224 39308 96.9 %-
Displacement parametersBiso max: 153.29 Å2 / Biso mean: 59.3475 Å2 / Biso min: 30.13 Å2
Baniso -1Baniso -2Baniso -3
1-14.2289 Å20 Å20.3716 Å2
2---25.043 Å20 Å2
3---10.8141 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.15→31.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4446 0 59 75 4580
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1619SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes111HARMONIC2
X-RAY DIFFRACTIONt_gen_planes643HARMONIC5
X-RAY DIFFRACTIONt_it4598HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion572SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5042SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4598HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6217HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion17.87
LS refinement shellResolution: 2.15→2.21 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.265 138 4.81 %
Rwork0.283 2729 -
all-2867 -
obs--96.67 %

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