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- PDB-5am7: FGFR1 mutant with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 5am7
TitleFGFR1 mutant with an inhibitor
ComponentsFIBROBLAST GROWTH FACTOR RECEPTOR 1
KeywordsTRANSFERASE / FGFR / CANCER / DOVITINIB / TKI258 / GATEKEEPER / GATE KEEPER
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 / auditory receptor cell development / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex 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 / 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 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of vascular endothelial cell proliferation / positive regulation of endothelial cell chemotaxis / skeletal system morphogenesis / positive regulation of mesenchymal cell proliferation / middle ear morphogenesis / ureteric bud development / cardiac muscle cell proliferation / 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 / cellular response to fibroblast growth factor stimulus / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / chondrocyte differentiation / calcium ion homeostasis / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / positive regulation of MAP kinase activity / positive regulation of neuron differentiation / SH2 domain binding / Signal transduction by L1 / stem cell proliferation / skeletal system development / positive regulation of cell differentiation / stem cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / stem cell factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / 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
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 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-38O / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.957 Å
AuthorsBunney, T.D. / Wan, S. / Thiyagarajan, N. / Sutto, L. / Williams, S.V. / Ashford, P. / Koss, H. / Knowles, M.A. / Gervasio, F.L. / Coveney, P.V. / Katan, M.
CitationJournal: Ebiomedicine / Year: 2015
Title: The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study
Authors: Bunney, T. / Wan, S. / Thiyagarajan, N. / Sutto, L. / Williams, S.V. / Ashford, P. / Koss, H. / Knowles, M.A. / Gervasio, F.L. / Coveney, P.V. / Katan, M.
History
DepositionMar 10, 2015Deposition site: PDBE / Processing site: PDBE
SupersessionMar 18, 2015ID: 4UX0
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)71,5737
Polymers70,6812
Non-polymers8915
Water3,909217
1
A: FIBROBLAST GROWTH FACTOR RECEPTOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8044
Polymers35,3411
Non-polymers4633
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)35,7693
Polymers35,3411
Non-polymers4282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)208.606, 57.835, 65.622
Angle α, β, γ (deg.)90.00, 107.40, 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 / FIBROBLAST GROWTH FACTOR 1


Mass: 35340.680 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, UNP RESIDUES 458-765 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PJ821 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): C41 LAMBDA 37
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-38O / 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one / Dovitinib


Mass: 392.429 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21FN6O
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 2.74 Å3/Da / Density % sol: 56 % / Description: NONE
Crystal growpH: 8
Details: 20 % PEG 5K MME, 0.1 M TRIS, PH 7.5, 0.2 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9795
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 8, 2014 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.96→28.92 Å / Num. obs: 45034 / % possible obs: 83.2 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 31.05 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 13
Reflection shellResolution: 1.96→2 Å / Redundancy: 2 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 1.9 / % possible all: 29.4

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4UWY

4uwy


Resolution: 1.957→28.917 Å / SU ML: 0.25 / σ(F): 1.33 / Phase error: 31.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2542 2256 5 %
Rwork0.1983 --
obs0.2011 44767 82.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.957→28.917 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4621 0 61 217 4899
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094795
X-RAY DIFFRACTIONf_angle_d1.3156482
X-RAY DIFFRACTIONf_dihedral_angle_d14.6971838
X-RAY DIFFRACTIONf_chiral_restr0.057705
X-RAY DIFFRACTIONf_plane_restr0.007822
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.957-1.99950.3942380.3031924X-RAY DIFFRACTION29
1.9995-2.0460.3315780.28651358X-RAY DIFFRACTION43
2.046-2.09710.3368760.27611639X-RAY DIFFRACTION52
2.0971-2.15380.28691020.24422011X-RAY DIFFRACTION62
2.1538-2.21720.32941640.25422325X-RAY DIFFRACTION74
2.2172-2.28870.59311270.41952337X-RAY DIFFRACTION74
2.2887-2.37050.2931260.2333090X-RAY DIFFRACTION95
2.3705-2.46540.26121800.22583170X-RAY DIFFRACTION100
2.4654-2.57750.29161810.22883187X-RAY DIFFRACTION100
2.5775-2.71330.27581750.22633210X-RAY DIFFRACTION100
2.7133-2.88310.26871610.22543208X-RAY DIFFRACTION100
2.8831-3.10550.28221500.22353227X-RAY DIFFRACTION100
3.1055-3.41760.25081840.20233189X-RAY DIFFRACTION99
3.4176-3.91110.22041810.17253115X-RAY DIFFRACTION97
3.9111-4.92360.20041780.14493201X-RAY DIFFRACTION99
4.9236-28.92060.2161550.16093320X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 226.9365 Å / Origin y: -11.1503 Å / Origin z: 28.711 Å
111213212223313233
T0.1807 Å2-0.0032 Å20.013 Å2-0.2663 Å2-0.0327 Å2--0.2535 Å2
L0.041 °20.0476 °20.1281 °2-0.3973 °2-0.3519 °2--0.8148 °2
S0.0132 Å °0.016 Å °-0.045 Å °0.0562 Å °-0.0376 Å °-0.0267 Å °-0.0295 Å °0.0442 Å °0.0243 Å °
Refinement TLS groupSelection details: ALL

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