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- PDB-6c1c: FGFR1 kinase complex with inhibitor SN37116 -

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Basic information

Entry
Database: PDB / ID: 6c1c
TitleFGFR1 kinase complex with inhibitor SN37116
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homologyImmunoglobulin-like fold / Ig-like domain profile. / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine kinase / Signaling by activated point mutants of FGFR1 / Protein kinase domain / Signaling by FGFR1 amplification mutants / PIP3 activates AKT signaling / PI3K Cascade / Protein kinase, ATP binding site ...Immunoglobulin-like fold / Ig-like domain profile. / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine kinase / Signaling by activated point mutants of FGFR1 / Protein kinase domain / Signaling by FGFR1 amplification mutants / PIP3 activates AKT signaling / PI3K Cascade / Protein kinase, ATP binding site / FGFR1c and Klotho ligand binding and activation / Protein kinase domain profile. / Tyrosine-protein kinase, catalytic domain / Fibroblast growth factor receptor 1, catalytic domain / Immunoglobulin-like domain superfamily / Fibroblast growth factor receptor family / Immunoglobulin domain / Tyrosine protein kinases specific active-site signature. / Protein kinases ATP-binding region signature. / FGFR1c ligand binding and activation / FGFR1b ligand binding and activation / Constitutive Signaling by Aberrant PI3K in Cancer / NCAM signaling for neurite out-growth / Signaling by plasma membrane FGFR1 fusions / Immunoglobulin / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Immunoglobulin I-set / RAF/MAP kinase cascade / Protein kinase-like domain superfamily / Tyrosine-protein kinase, active site / Immunoglobulin-like domain / Immunoglobulin subtype / Signaling by FGFR1 in disease / Negative regulation of FGFR1 signaling / Immunoglobulin subtype 2 / FRS-mediated FGFR1 signaling / PI-3K cascade:FGFR1 / SHC-mediated cascade:FGFR1 / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / Signal transduction by L1 / Immunoglobulin I-set domain / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / positive regulation of parathyroid hormone secretion / regulation of extrinsic apoptotic signaling pathway in absence of ligand / regulation of phosphate transport / auditory receptor cell development / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / vitamin D3 metabolic process / regulation of lateral mesodermal cell fate specification / positive regulation of endothelial cell chemotaxis to fibroblast growth factor / receptor-receptor interaction / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / middle ear morphogenesis / chordate embryonic development / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / paraxial mesoderm development / fibroblast growth factor-activated receptor activity / branching involved in salivary gland morphogenesis / lung-associated mesenchyme development / organ induction / mesenchymal cell differentiation / positive regulation of phospholipase activity / embryonic limb morphogenesis / fibroblast growth factor binding / skeletal system morphogenesis / positive regulation of vascular endothelial cell proliferation / regulation of cell differentiation / outer ear morphogenesis / inner ear morphogenesis / ureteric bud development / midbrain development / positive regulation of mesenchymal cell proliferation / chondrocyte differentiation / positive regulation of blood vessel endothelial cell migration / cell maturation / positive regulation of phospholipase C activity / SH2 domain binding / 1-phosphatidylinositol-3-kinase activity / fibroblast growth factor receptor signaling pathway / phosphatidylinositol-mediated signaling / skeletal system development / positive regulation of neuron projection development / positive regulation of cell differentiation / positive regulation of neuron differentiation / sensory perception of sound / neuron migration / positive regulation of cardiac muscle cell proliferation / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / nervous system development / peptidyl-tyrosine phosphorylation / Ras guanyl-nucleotide exchange factor activity / positive regulation of MAP kinase activity / in utero embryonic development / phosphatidylinositol-4,5-bisphosphate 3-kinase activity / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration
Function and homology information
Specimen sourceHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / 2.15 Å resolution
AuthorsYosaatmadja, Y. / Smaill, J.B. / Squire, C.J.
Funding supportNew Zealand, 1 items
OrganizationGrant numberCountry
Health Research Council of New ZealandNew Zealand
CitationJournal: To Be Published
Title: Understanding the structural requirements for covalent inhibition of FGFR1-3
Authors: Yosaatmadja, Y. / Squire, C.J. / Patterson, A.V. / Smaill, J.B.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jan 4, 2018 / Release: Jan 16, 2019

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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)72,0685
Polyers70,7072
Non-polymers1,3613
Water97354
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9862
Polyers35,3541
Non-polymers6331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0823
Polyers35,3541
Non-polymers7292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)213.293, 52.035, 66.045
Angle α, β, γ (deg.)90.00, 107.08, 90.00
Int Tables number5
Space group name H-MC 1 2 1

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Components

#1: Protein/peptide Fibroblast growth factor receptor 1 / / 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: 35353.613 Da / Num. of mol.: 2 / Fragment: UNP residues 457-763 / Mutation: C486A, C582S / Source: (gene. exp.) Homo sapiens (human)
Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFRFibroblast growth factor receptor 1
Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-YY6 / 7-(cyclohexylamino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{(3S)-1-[(2E)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one


Mass: 632.581 Da / Num. of mol.: 2 / Formula: C30H39Cl2N7O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Formula: SO4 / Sulfate
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / Formula: H2O / Water

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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: 2.48 / Density percent sol: 50.35 %
Crystal growTemp: 291 K / Method: vapor diffusion, hanging drop
Details: 20% MPEG 5000, 0.1 M sodium cacodylate pH 7.5, 0.2 M ammonium sulfate

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Data collection

DiffractionMean temperature: 110 kelvins
SourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Collection date: Dec 5, 2014
RadiationDiffraction protocol: SINGLE WAVELENGTH / Monochromatic or laue m l: M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionD resolution high: 2.15 Å / D resolution low: 19.51 Å / Number obs: 37994 / CC half: 0.999 / Rmerge I obs: 0.087 / Rpim I all: 0.034 / NetI over sigmaI: 19.8 / Redundancy: 7.5 % / Percent possible obs: 99.9
Reflection shellHighest resolution: 2.15 Å / Lowest resolution: 2.22 Å / MeanI over sigI obs: 1.7 / Number unique all: 3287 / Number unique obs: 3287 / CC half: 0.764 / Rpim I all: 0.494 / Redundancy: 7.5 % / Percent possible all: 1

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefineMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WUN
Correlation coeff Fo to Fc: 0.945 / Correlation coeff Fo to Fc free: 0.917 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS / Overall SU B: 7.118 / Overall SU ML: 0.179 / R Free selection details: RANDOM / Cross valid method: THROUGHOUT / Overall ESU R: 0.239 / Overall ESU R Free: 0.206
Solvent computationSolvent ion probe radii: 0.8 Å / Solvent shrinkage radii: 0.8 Å / Solvent vdw probe radii: 1.2 Å
Displacement parametersB iso mean: 42.59 Å2 / Aniso B11: -0.44 Å2 / Aniso B12: 0 Å2 / Aniso B13: -0.42 Å2 / Aniso B22: 1.43 Å2 / Aniso B23: 0 Å2 / Aniso B33: -0.61 Å2
Least-squares processR factor R free: 0.27 / R factor R work: 0.226 / R factor obs: 0.228 / Highest resolution: 2.15 Å / Lowest resolution: 19.51 Å / Number reflection R free: 1889 / Number reflection obs: 36092 / Percent reflection R free: 5 / Percent reflection obs: 99.8
Refine hist #LASTHighest resolution: 2.15 Å / Lowest resolution: 19.51 Å
Number of atoms included #LASTProtein: 4155 / Nucleic acid: 0 / Ligand: 91 / Solvent: 54 / Total: 4300
Refine LS restraints
Refine IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0204398
X-RAY DIFFRACTIONr_bond_other_d0.0030.0204167
X-RAY DIFFRACTIONr_angle_refined_deg1.3442.0035979
X-RAY DIFFRACTIONr_angle_other_deg0.8683.0069592
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7315.000546
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.75524.368174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.00915.000724
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.90115.00025
X-RAY DIFFRACTIONr_chiral_restr0.0810.200669
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214888
X-RAY DIFFRACTIONr_gen_planes_other0.0010.020913
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_it2.3424.3392193
X-RAY DIFFRACTIONr_mcbond_other2.3424.3382192
X-RAY DIFFRACTIONr_mcangle_it3.6906.4802733
X-RAY DIFFRACTIONr_mcangle_other3.6896.4812734
X-RAY DIFFRACTIONr_scbond_it2.3384.4492205
X-RAY DIFFRACTIONr_scbond_other2.3344.4402202
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.7336.5983240
X-RAY DIFFRACTIONr_long_range_B_refined5.25533.3104860
X-RAY DIFFRACTIONr_long_range_B_other5.24833.3104848
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS shellHighest resolution: 2.15 Å / R factor R free: 0.338 / R factor R work: 0.311 / Lowest resolution: 2.21 Å / Number reflection R free: 157 / Number reflection R work: 2648 / Total number of bins used: 20 / Percent reflection obs: 99.96

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