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- PDB-4rwl: Crystal structure of FGFR1 (C488A, C584C) in complex with 6-(7-((... -

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Basic information

Entry
Database: PDB / ID: 4rwl
TitleCrystal structure of FGFR1 (C488A, C584C) in complex with 6-(7-((1-aminocyclopropyl) methoxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide (E3810)
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / receptor tyrosine kinase / gatekeeper mutation / proto-oncogene / kinase / 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 / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / diphosphate metabolic process / ventricular zone neuroblast division / vitamin D3 metabolic process / regulation of phosphate transport ...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 / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / diphosphate metabolic process / ventricular zone neuroblast division / 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 / auditory receptor cell development / Epithelial-Mesenchymal Transition (EMT) during gastrulation / chordate embryonic development / positive regulation of parathyroid hormone secretion / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / positive regulation of phospholipase activity / mesenchymal cell proliferation / paraxial mesoderm development / lung-associated mesenchyme development / FGFR1b ligand binding and activation / Signaling by activated point mutants of FGFR1 / organ induction / FGFR1c ligand binding and activation / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / cell projection assembly / cellular response to fibroblast growth factor stimulus / skeletal system morphogenesis / outer ear morphogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / embryonic limb morphogenesis / inner ear morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / midbrain development / cardiac muscle cell proliferation / fibroblast growth factor binding / regulation of cell differentiation / positive regulation of stem cell proliferation / PI-3K cascade:FGFR1 / Formation of paraxial mesoderm / phosphatidylinositol-mediated signaling / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / cell maturation / 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 / positive regulation of MAP kinase activity / neuron migration / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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-3ZC / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.193 Å
AuthorsSohl, C.D. / Anderson, K.S.
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.
Authors: Sohl, C.D. / Ryan, M.R. / Luo, B. / Frey, K.M. / Anderson, K.S.
History
DepositionDec 4, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2015Provider: repository / Type: Initial release
Revision 1.1May 27, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 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 / 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

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)72,9934
Polymers72,4532
Non-polymers5402
Water90150
1
A: Fibroblast growth factor receptor 1


Theoretical massNumber of molelcules
Total (without water)36,2271
Polymers36,2271
Non-polymers00
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)36,7663
Polymers36,2271
Non-polymers5402
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)207.166, 57.860, 65.658
Angle α, β, γ (deg.)90.000, 107.190, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and segidA0
211chain B and segidB0

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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: 36226.602 Da / Num. of mol.: 2 / Fragment: Residues 458-765 / Mutation: C488A, C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BFGFR, CEK, FGFBR, FGFR1, FLG, FLT2, HBGFR / Plasmid: pET-28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3ZC / 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-N-methylnaphthalene-1-carboxamide


Mass: 443.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25N3O4 / Comment: inhibitor*YM
#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.: 50 / 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: 2.59 Å3/Da / Density % sol: 52.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 0.1 M sodium cacodylate pH 6.6, 34% PEG 8000, 0.2 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 22, 2014 / Details: monochrometer
RadiationMonochromator: Cryogenically cooled double crystal monochrometer with horizontal focusing sagittal bend second mono crystal with 4:1 magnification ratio and vertically focusing mirror.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 38180 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 40.93 Å2 / Rsym value: 0.086 / Net I/σ(I): 31.88
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.19-2.233.40.371190
2.23-2.273.80.3351100
2.27-2.313.80.3031100
2.31-2.363.80.2581100
2.36-2.413.80.2241100
2.41-2.473.80.2071100
2.47-2.533.80.1831100
2.53-2.63.80.1651100
2.6-2.673.80.151100
2.67-2.763.80.1231100
2.76-2.863.80.1161100
2.86-2.973.80.11100
2.97-3.113.80.0931100
3.11-3.273.80.0821100
3.27-3.483.80.0791100
3.48-3.743.80.075199.9
3.74-4.123.70.081199.7
4.12-4.723.60.079198.8
4.72-5.943.60.07199.7
5.94-503.50.062193.7

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4NKA

4nka


Resolution: 2.193→32.986 Å / SU ML: 0.27 / σ(F): 1.34 / Phase error: 28.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2555 1914 5.01 %
Rwork0.2068 --
obs0.2093 38169 99.47 %
all-38169 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.8932 Å2
Refinement stepCycle: LAST / Resolution: 2.193→32.986 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4363 0 38 50 4451
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094491
X-RAY DIFFRACTIONf_angle_d1.086099
X-RAY DIFFRACTIONf_dihedral_angle_d12.9241640
X-RAY DIFFRACTIONf_chiral_restr0.046685
X-RAY DIFFRACTIONf_plane_restr0.006780
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDType
11A2496X-RAY DIFFRACTIONTORSIONAL
12B2496X-RAY DIFFRACTIONTORSIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.193-2.24810.30271360.25192556X-RAY DIFFRACTION99
2.2481-2.30880.27861330.23982568X-RAY DIFFRACTION100
2.3088-2.37670.2881340.22712582X-RAY DIFFRACTION100
2.3767-2.45340.3131360.23262568X-RAY DIFFRACTION100
2.4534-2.54110.3041390.22472597X-RAY DIFFRACTION100
2.5411-2.64280.32251380.232593X-RAY DIFFRACTION100
2.6428-2.7630.27371380.22532599X-RAY DIFFRACTION100
2.763-2.90860.30651320.23442588X-RAY DIFFRACTION100
2.9086-3.09070.28211320.23862586X-RAY DIFFRACTION100
3.0907-3.32910.28531400.23212609X-RAY DIFFRACTION100
3.3291-3.66380.26091370.21412607X-RAY DIFFRACTION100
3.6638-4.1930.22191380.18432604X-RAY DIFFRACTION100
4.193-5.27920.20711430.16912604X-RAY DIFFRACTION99
5.2792-32.98970.23331380.19092594X-RAY DIFFRACTION96

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