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- PDB-5vnd: Crystal structure of FGFR1-Y563C (FGFR4 surrogate) covalently bou... -

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Basic information

Entry
Database: PDB / ID: 5vnd
TitleCrystal structure of FGFR1-Y563C (FGFR4 surrogate) covalently bound to H3B-6527
ComponentsFibroblast growth factor receptor 1
Keywordstransferase/transferase inhibitor / FGFR4 / H3B-56527 / Covalent compound / 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 / diphosphate metabolic process / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification ...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 / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / positive regulation of endothelial cell chemotaxis to fibroblast growth factor / receptor-receptor interaction / response to sodium phosphate / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of parathyroid hormone secretion / chordate embryonic development / mesenchymal cell proliferation / paraxial mesoderm development / fibroblast growth factor receptor activity / FGFR1b ligand binding and activation / branching involved in salivary gland morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / cell projection assembly / phosphatidylinositol-mediated signaling / outer ear morphogenesis / middle ear morphogenesis / embryonic limb morphogenesis / skeletal system morphogenesis / ureteric bud development / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / inner ear morphogenesis / midbrain development / fibroblast growth factor binding / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / regulation of cell differentiation / PI-3K cascade:FGFR1 / PI3K Cascade / epithelial to mesenchymal transition / positive regulation of blood vessel endothelial cell migration / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / positive regulation of phospholipase C activity / SHC-mediated cascade:FGFR1 / cell maturation / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / positive regulation of neuron differentiation / Signaling by FGFR1 in disease / NCAM signaling for neurite out-growth / SH2 domain binding / Signal transduction by L1 / skeletal system development / stem cell proliferation / stem cell differentiation / positive regulation of cell differentiation / sensory perception of sound / Negative regulation of FGFR1 signaling / neuron migration / positive regulation of MAP kinase activity / positive regulation of neuron projection development / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / cell migration / PIP3 activates AKT signaling / heparin binding / gene expression / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / cytoplasmic vesicle / RAF/MAP kinase cascade / angiogenesis / protein tyrosine kinase activity / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / 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
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 / Tyrosine 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; 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-9ES / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsTsai, J.H.C. / Reynolds, D. / Fekkes, P. / Smith, P. / Larsen, N.A.
CitationJournal: Cancer Res. / Year: 2017
Title: H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma.
Authors: Joshi, J.J. / Coffey, H. / Corcoran, E. / Tsai, J. / Huang, C.L. / Ichikawa, K. / Prajapati, S. / Hao, M.H. / Bailey, S. / Wu, J. / Rimkunas, V. / Karr, C. / Subramanian, V. / Kumar, P. / ...Authors: Joshi, J.J. / Coffey, H. / Corcoran, E. / Tsai, J. / Huang, C.L. / Ichikawa, K. / Prajapati, S. / Hao, M.H. / Bailey, S. / Wu, J. / Rimkunas, V. / Karr, C. / Subramanian, V. / Kumar, P. / MacKenzie, C. / Hurley, R. / Satoh, T. / Yu, K. / Park, E. / Rioux, N. / Kim, A. / Lai, W.G. / Yu, L. / Zhu, P. / Buonamici, S. / Larsen, N. / Fekkes, P. / Wang, J. / Warmuth, M. / Reynolds, D.J. / Smith, P.G. / Selvaraj, A.
History
DepositionApr 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 5, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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)72,72923
Polymers70,1512
Non-polymers2,57821
Water4,414245
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,45813
Polymers35,0751
Non-polymers1,38212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,27110
Polymers35,0751
Non-polymers1,1969
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-44 kcal/mol
Surface area29390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)208.494, 58.925, 65.935
Angle α, β, γ (deg.)90.00, 107.59, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: TYR / Beg label comp-ID: TYR / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: 0 / Auth seq-ID: 463 - 765 / Label seq-ID: 7 - 309

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Fibroblast growth factor receptor 1 / / FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 ...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: 35075.309 Da / Num. of mol.: 2 / Fragment: unp residues 458-765 / Mutation: C486A, Y561C, C582S
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) / Strain (production host): DE3 star
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-9ES / N-{2-[(6-{[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](methyl)amino}pyrimidin-4-yl)amino]-5-(4-ethylpiperazin-1-yl)phenyl}propanamide


Mass: 631.553 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H36Cl2N8O4
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 245 / 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: 2.75 Å3/Da / Density % sol: 55.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 20% PEG10000, 0.1M MES pH6.2, 0.3M Ammonium Sulphate, 5% Ethylene glycol

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.98 Å
DetectorType: RAYONIX / Detector: CCD / Date: Nov 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.08→99.37 Å / Num. obs: 46172 / % possible obs: 99.9 % / Redundancy: 3.8 % / Net I/σ(I): 8.6
Reflection shellResolution: 2.08→2.15 Å / Redundancy: 3.8 % / Rmerge(I) obs: 1 / Mean I/σ(I) obs: 3.8 / Num. measured all: 4591 / Num. unique obs: 4550 / Rpim(I) all: 0.532 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4V05

4v05


Resolution: 2.2→99.37 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.947 / SU B: 5.53 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R: 0.221 / ESU R Free: 0.186 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22333 1989 5.1 %RANDOM
Rwork0.17822 ---
obs0.18059 37022 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 51.934 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å20 Å2-0.81 Å2
2--2.45 Å20 Å2
3----1.46 Å2
Refinement stepCycle: 1 / Resolution: 2.2→99.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4691 0 166 245 5102
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0194949
X-RAY DIFFRACTIONr_bond_other_d0.0070.024760
X-RAY DIFFRACTIONr_angle_refined_deg1.8962.0086674
X-RAY DIFFRACTIONr_angle_other_deg2.13310962
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4115595
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.69224.354209
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.63915857
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5931530
X-RAY DIFFRACTIONr_chiral_restr0.110.2726
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0215458
X-RAY DIFFRACTIONr_gen_planes_other0.0130.021054
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_it4.724.9452386
X-RAY DIFFRACTIONr_mcbond_other4.7194.9472387
X-RAY DIFFRACTIONr_mcangle_it6.6727.3862978
X-RAY DIFFRACTIONr_mcangle_other6.6677.3842977
X-RAY DIFFRACTIONr_scbond_it5.8395.4712563
X-RAY DIFFRACTIONr_scbond_other5.8395.4712563
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.6447.9763696
X-RAY DIFFRACTIONr_long_range_B_refined11.33939.7025634
X-RAY DIFFRACTIONr_long_range_B_other11.33839.7075635
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 34034 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.274 149 -
Rwork0.26 2717 -
obs--99.62 %

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