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- PDB-8jmz: FGFR1 kinase domain with sulfatinib -

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Basic information

Entry
Database: PDB / ID: 8jmz
TitleFGFR1 kinase domain with sulfatinib
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/INHIBITOR / Fibroblast growth factor receptor 1 / 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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...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 / diphosphate metabolic process / Signaling by plasma membrane FGFR1 fusions / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / vitamin D3 metabolic process / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / receptor-receptor interaction / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / chordate embryonic development / auditory receptor cell development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / cardiac muscle cell proliferation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / stem cell proliferation / Signal transduction by L1 / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / Negative regulation of FGFR1 signaling / sensory perception of sound / positive regulation of neuron projection development / receptor protein-tyrosine kinase / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / postsynapse / positive regulation of MAPK cascade / positive regulation of cell population proliferation / glutamatergic synapse
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 / 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
: / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.988 Å
AuthorsChen, X.J. / Lin, Q.M. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82172654 China
National Natural Science Foundation of China (NSFC)82202920 China
CitationJournal: Commun Chem / Year: 2024
Title: Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R.
Authors: Lin, Q. / Dai, S. / Qu, L. / Lin, H. / Guo, M. / Wei, H. / Chen, Y. / Chen, X.
History
DepositionJun 5, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / pdbx_entry_details
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)72,53915
Polymers70,5292
Non-polymers2,01013
Water8,017445
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4149
Polymers35,2651
Non-polymers1,1498
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1256
Polymers35,2651
Non-polymers8615
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)211.458, 49.873, 66.691
Angle α, β, γ (deg.)90.00, 107.57, 90.00
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 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35264.520 Da / Num. of mol.: 2 / Mutation: C129S
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 (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-UKI / Sulfatinib / N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide


Mass: 480.583 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 445 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.46 Å3/Da / Density % sol: 49.98 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.1 M MES pH 6.6,34% PEG 8000,0.2 M ammonium sulfate

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.587 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Jul 31, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.587 Å / Relative weight: 1
ReflectionResolution: 1.988→50 Å / Num. obs: 45822 / % possible obs: 100 % / Redundancy: 6.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.06755 / Rrim(I) all: 0.07307 / Net I/σ(I): 19.43
Reflection shellResolution: 1.988→2.059 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.3188 / Mean I/σ(I) obs: 4.08 / Num. unique obs: 4353 / CC1/2: 0.94 / Rrim(I) all: 0.3527 / % possible all: 96

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WCL

7wcl


Resolution: 1.988→40.048 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2048 2356 5.14 %
Rwork0.1634 --
obs0.1656 45820 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.988→40.048 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4701 0 125 445 5271
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0134933
X-RAY DIFFRACTIONf_angle_d1.3396689
X-RAY DIFFRACTIONf_dihedral_angle_d13.9761859
X-RAY DIFFRACTIONf_chiral_restr0.059719
X-RAY DIFFRACTIONf_plane_restr0.007849
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.988-2.02850.22681310.17782374X-RAY DIFFRACTION94
2.0285-2.07260.22911350.17022551X-RAY DIFFRACTION99
2.0726-2.12090.22561130.1672533X-RAY DIFFRACTION100
2.1209-2.17390.21441370.15762564X-RAY DIFFRACTION100
2.1739-2.23270.21461380.1542538X-RAY DIFFRACTION100
2.2327-2.29840.21931390.16822557X-RAY DIFFRACTION100
2.2984-2.37250.24051200.16042596X-RAY DIFFRACTION100
2.3725-2.45730.2021450.16352526X-RAY DIFFRACTION100
2.4573-2.55570.24931330.1692564X-RAY DIFFRACTION100
2.5557-2.6720.22561420.17212546X-RAY DIFFRACTION100
2.672-2.81280.23211090.17492581X-RAY DIFFRACTION100
2.8128-2.9890.21511520.18122552X-RAY DIFFRACTION100
2.989-3.21970.21131520.17292570X-RAY DIFFRACTION100
3.2197-3.54350.18021190.162612X-RAY DIFFRACTION100
3.5435-4.05590.1941520.14572556X-RAY DIFFRACTION100
4.0559-5.10830.16941640.14662591X-RAY DIFFRACTION100
5.1083-40.0480.20741750.17542653X-RAY DIFFRACTION100

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