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- PDB-3rhx: Crystal structure of the catalytic domain of FGFR1 kinase in comp... -

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Basic information

Entry
Database: PDB / ID: 3rhx
TitleCrystal structure of the catalytic domain of FGFR1 kinase in complex with ARQ 069
ComponentsBasic fibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FGFR1 kinase / FGFR2 kinase / inactive conformation / kinase-inhibitor complex / 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-3RH / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsEathiraj, S. / Palma, R. / Hirschi, M. / Volckova, E. / Nakuci, E. / Castro, J. / Chen, C.R. / Chan, T.C. / France, D.S. / Ashwell, M.A.
CitationJournal: J.Biol.Chem. / Year: 2011
Title: A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor.
Authors: Eathiraj, S. / Palma, R. / Hirschi, M. / Volckova, E. / Nakuci, E. / Castro, J. / Chen, C.R. / Chan, T.C. / France, D.S. / Ashwell, M.A.
History
DepositionApr 12, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 19, 2011Group: Database references
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Basic fibroblast growth factor receptor 1
A: Basic fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,76910
Polymers69,8162
Non-polymers9538
Water8,791488
1
B: Basic fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3404
Polymers34,9081
Non-polymers4313
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: Basic fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4306
Polymers34,9081
Non-polymers5225
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.430, 57.865, 65.686
Angle α, β, γ (deg.)90.00, 107.22, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Basic fibroblast growth factor receptor 1 / FGFR-1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / Proto-oncogene c-Fgr


Mass: 34908.078 Da / Num. of mol.: 2 / Fragment: UNP residues 461-765 / Mutation: C488A, C584S
Source method: isolated from a genetically manipulated source
Details: Bicistronically co-expressed with lambda phosphatase
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, FGFBR, FLG, FLT2 / Production host: Escherichia coli (E. coli) / Strain (production host): Codon Plus BL21(DE3)-RILP
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3RH / (6S)-6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-amine


Mass: 273.332 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N3
#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.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 488 / 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: 2.71 Å3/Da / Density % sol: 54.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: PEG 10000, 0.3M (NH4)2SO4, 5% ethylene glycol, 100mM MES, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 3, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.01→50 Å / Num. obs: 59198 / % possible obs: 97.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.01→8 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.915 / SU B: 4.774 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26167 2440 5.1 %RANDOM
Rwork0.2014 ---
obs0.20456 45487 97.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.141 Å2
Baniso -1Baniso -2Baniso -3
1--1.87 Å20 Å2-0.74 Å2
2--3.85 Å20 Å2
3----2.42 Å2
Refinement stepCycle: LAST / Resolution: 2.01→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4439 0 67 488 4994
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0224563
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8541.9886173
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4995558
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.06223.698192
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.89715807
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8561533
X-RAY DIFFRACTIONr_chiral_restr0.130.2683
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213403
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.231.52811
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.15724511
X-RAY DIFFRACTIONr_scbond_it3.38931752
X-RAY DIFFRACTIONr_scangle_it5.1984.51662
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.01→2.059 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 145 -
Rwork0.267 2926 -
obs--88.96 %

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