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- PDB-6nvl: FGFR1 complex with N-(2-((5-((2,6-dichloro-3,5-dimethoxybenzyl)ox... -

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Basic information

Entry
Database: PDB / ID: 6nvl
TitleFGFR1 complex with N-(2-((5-((2,6-dichloro-3,5-dimethoxybenzyl)oxy)pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE
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 / vitamin D3 metabolic process / cementum mineralization / 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 / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / chordate embryonic development / receptor-receptor interaction / auditory receptor cell development / mesenchymal cell proliferation / positive regulation of parathyroid hormone secretion / 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 / skeletal system morphogenesis / middle ear morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / positive regulation of stem cell proliferation / Formation of paraxial mesoderm / midbrain development / positive regulation of MAP kinase activity / fibroblast growth factor binding / 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 / heparin binding / MAPK cascade / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / cytoplasmic vesicle / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-XL6 / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsLin, X. / Smaill, J.B. / Squire, C.J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4.
Authors: Lin, X. / Yosaatmadja, Y. / Kalyukina, M. / Middleditch, M.J. / Zhang, Z. / Lu, X. / Ding, K. / Patterson, A.V. / Smaill, J.B. / Squire, C.J.
History
DepositionFeb 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 11, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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
C: Fibroblast growth factor receptor 1
D: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,11513
Polymers140,6704
Non-polymers2,4469
Water75742
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7553
Polymers35,1671
Non-polymers5872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7553
Polymers35,1671
Non-polymers5872
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6592
Polymers35,1671
Non-polymers4911
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9475
Polymers35,1671
Non-polymers7804
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.331, 83.701, 102.604
Angle α, β, γ (deg.)90.00, 113.60, 90.00
Int Tables number4
Space group name H-MP1211

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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: 35167.406 Da / Num. of mol.: 4 / Mutation: C584S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Plasmid: pETDuet-1 / Production host: Escherichia coli (E. coli)
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-XL6 / N-[2-({5-[(2,6-dichloro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl}amino)-3-methylphenyl]propanamide


Mass: 491.367 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H24Cl2N4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O
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: 2.61 Å3/Da / Density % sol: 52.89 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 90 mM NPS salt mixture (30 mM sodium nitrate, 30 mM sodium phosphate dibasic, 30 mM ammonium sulfatesulfate), 100 mM HEPES/MOPS pH 7.5, and 50% v/v of a precipitant mixture of 40% v/v PEG ...Details: 90 mM NPS salt mixture (30 mM sodium nitrate, 30 mM sodium phosphate dibasic, 30 mM ammonium sulfatesulfate), 100 mM HEPES/MOPS pH 7.5, and 50% v/v of a precipitant mixture of 40% v/v PEG 500 MME and 20 % w/v PEG 20,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.7→47.06 Å / Num. obs: 40011 / % possible obs: 100 % / Redundancy: 6.8 % / CC1/2: 0.971 / Net I/σ(I): 4.8
Reflection shellResolution: 2.7→2.81 Å / Redundancy: 6.3 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 4482 / CC1/2: 0.505 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WUN

4wun


Resolution: 2.7→47.06 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.886 / SU B: 13.836 / SU ML: 0.28 / Cross valid method: THROUGHOUT / ESU R: 0.802 / ESU R Free: 0.339 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26289 1913 4.8 %RANDOM
Rwork0.21272 ---
obs0.21514 38083 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 37.898 Å2
Baniso -1Baniso -2Baniso -3
1--2.14 Å20 Å2-0.48 Å2
2--0.78 Å2-0 Å2
3---1.29 Å2
Refinement stepCycle: 1 / Resolution: 2.7→47.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8173 0 157 42 8372
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0138533
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177875
X-RAY DIFFRACTIONr_angle_refined_deg1.2411.64311593
X-RAY DIFFRACTIONr_angle_other_deg1.1111.57518163
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.14351065
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.78522.353374
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.714151374
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3941547
X-RAY DIFFRACTIONr_chiral_restr0.0460.21103
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029445
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021688
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_it1.664.1964311
X-RAY DIFFRACTIONr_mcbond_other1.6614.1964310
X-RAY DIFFRACTIONr_mcangle_it2.8236.275359
X-RAY DIFFRACTIONr_mcangle_other2.8236.2715360
X-RAY DIFFRACTIONr_scbond_it1.6454.2594222
X-RAY DIFFRACTIONr_scbond_other1.6454.2594223
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.7626.3466235
X-RAY DIFFRACTIONr_long_range_B_refined4.65647.1219046
X-RAY DIFFRACTIONr_long_range_B_other4.65647.1279047
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 148 -
Rwork0.298 2773 -
obs--99.73 %

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