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- PDB-8xz7: FGFR1 kinase domain with a covalent inhibitor 10h -

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Basic information

Entry
Database: PDB / ID: 8xz7
TitleFGFR1 kinase domain with a covalent inhibitor 10h
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / Fibroblast growth factor receptor 1
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 / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process ...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 / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / 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 / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / auditory receptor cell development / chordate embryonic development / positive regulation of phospholipase activity / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / regulation of postsynaptic density assembly / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / 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 / skeletal system morphogenesis / cardiac muscle cell proliferation / middle ear morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / Formation of paraxial mesoderm / positive regulation of stem cell proliferation / midbrain development / fibroblast growth factor binding / regulation of cell differentiation / PI3K Cascade / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / chondrocyte differentiation / positive regulation of MAP kinase activity / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / cellular response to fibroblast growth factor stimulus / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / positive regulation of neuron differentiation / NCAM signaling for neurite out-growth / fibroblast growth factor receptor activity / SH2 domain binding / Signal transduction by L1 / stem cell proliferation / skeletal system development / stem cell differentiation / positive regulation of cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / peptidyl-tyrosine phosphorylation / receptor protein-tyrosine kinase / positive regulation of neuron projection development / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / receptor complex / postsynapse / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / protein phosphorylation / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsChen, X.J. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82202920 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.
Authors: Deng, W. / Chen, X. / Liang, H. / Song, X. / Xiang, S. / Guo, J. / Tu, Z. / Zhou, Y. / Chen, Y. / Lu, X.
History
DepositionJan 20, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _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
B: Fibroblast growth factor receptor 1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9609
Polymers70,5292
Non-polymers1,4317
Water6,521362
1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0285
Polymers35,2651
Non-polymers7644
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9324
Polymers35,2651
Non-polymers6683
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)210.340, 49.630, 66.740
Angle α, β, γ (deg.)90.00, 106.94, 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 #1/H766 (bacteria)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-A1LWW / 5-azanyl-3-[2-[4,6-bis(fluoranyl)-2-methyl-3~{H}-benzimidazol-5-yl]ethynyl]-1-[[3-(prop-2-enoylamino)phenyl]methyl]pyrazole-4-carboxamide


Mass: 475.450 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19F2N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 362 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.37 Å3/Da / Density % sol: 48.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 18% PEG 8000, 0.2 M Li2SO4, and 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.75→26.14 Å / Num. obs: 64921 / % possible obs: 97.07 % / Redundancy: 6.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.1319 / Rrim(I) all: 0.1438 / Net I/σ(I): 12.08
Reflection shellResolution: 1.75→1.813 Å / Redundancy: 6.5 % / Rmerge(I) obs: 1.671 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 6382 / CC1/2: 0.637 / % possible all: 95.93

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
xia2data reduction
xia2data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WCL

7wcl


Resolution: 1.75→26.14 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2251 3228 4.97 %
Rwork0.1865 --
obs0.1884 64917 97.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→26.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4736 0 95 362 5193
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094937
X-RAY DIFFRACTIONf_angle_d1.0376695
X-RAY DIFFRACTIONf_dihedral_angle_d8.353664
X-RAY DIFFRACTIONf_chiral_restr0.062720
X-RAY DIFFRACTIONf_plane_restr0.008855
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.780.28181350.28022662X-RAY DIFFRACTION96
1.78-1.80.27551340.26952637X-RAY DIFFRACTION96
1.8-1.830.31631430.24952650X-RAY DIFFRACTION97
1.83-1.870.34731420.23942605X-RAY DIFFRACTION96
1.87-1.90.29131350.23022686X-RAY DIFFRACTION97
1.9-1.940.30211400.23422606X-RAY DIFFRACTION97
1.94-1.970.27441580.21542661X-RAY DIFFRACTION97
1.97-2.020.23621470.20532607X-RAY DIFFRACTION97
2.02-2.060.22641310.20782712X-RAY DIFFRACTION97
2.06-2.120.26141340.20332651X-RAY DIFFRACTION97
2.12-2.170.25351670.19272651X-RAY DIFFRACTION97
2.17-2.240.2361350.18942684X-RAY DIFFRACTION97
2.24-2.310.23071120.19242707X-RAY DIFFRACTION97
2.31-2.390.23881220.18562708X-RAY DIFFRACTION98
2.39-2.490.25671170.19912712X-RAY DIFFRACTION98
2.49-2.60.26951540.19242688X-RAY DIFFRACTION98
2.6-2.740.22771670.19512665X-RAY DIFFRACTION98
2.74-2.910.21751530.19172705X-RAY DIFFRACTION98
2.91-3.130.21421470.19022676X-RAY DIFFRACTION98
3.13-3.450.24141600.17832702X-RAY DIFFRACTION98
3.45-3.950.1641360.15962752X-RAY DIFFRACTION98
3.95-4.970.16671350.1522763X-RAY DIFFRACTION98
4.97-26.140.2321240.18232799X-RAY DIFFRACTION96

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