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- PDB-3ri1: Crystal structure of the catalytic domain of FGFR2 kinase in comp... -

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Basic information

Entry
Database: PDB / ID: 3ri1
TitleCrystal structure of the catalytic domain of FGFR2 kinase in complex with ARQ 069
ComponentsFibroblast growth factor receptor 2
KeywordsTransferase/Transferase Inhibitor / FGFR1 kinase / FGFR2 kinase / inactive conformation / kinase-inhibitor complex / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development ...Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / otic vesicle formation / prostate gland morphogenesis / regulation of smooth muscle cell differentiation / orbitofrontal cortex development / regulation of morphogenesis of a branching structure / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / branching morphogenesis of a nerve / embryonic organ morphogenesis / endochondral bone growth / morphogenesis of embryonic epithelium / epidermis morphogenesis / bud elongation involved in lung branching / positive regulation of epithelial cell proliferation involved in lung morphogenesis / pyramidal neuron development / membranous septum morphogenesis / reproductive structure development / limb bud formation / lung lobe morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell differentiation / branching involved in prostate gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in labyrinthine layer morphogenesis / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / regulation of osteoblast proliferation / Phospholipase C-mediated cascade; FGFR2 / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / embryonic pattern specification / outflow tract septum morphogenesis / positive regulation of phospholipase activity / lung-associated mesenchyme development / mesodermal cell differentiation / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / digestive tract development / bone morphogenesis / skeletal system morphogenesis / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / Signaling by FGFR2 IIIa TM / inner ear morphogenesis / organ growth / midbrain development / hair follicle morphogenesis / lung alveolus development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / fibroblast growth factor binding / PI-3K cascade:FGFR2 / bone mineralization / prostate epithelial cord elongation / positive regulation of cell division / excitatory synapse / positive regulation of Wnt signaling pathway / PI3K Cascade / negative regulation of keratinocyte proliferation / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / cell fate commitment / embryonic organ development / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / regulation of ERK1 and ERK2 cascade / post-embryonic development / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation
Similarity search - Function
Fibroblast growth factor receptor family / 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 ...Fibroblast growth factor receptor family / 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 / 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-3RH / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsEathiraj, S. / Palma, R. / Hirschi, M. / Volckova, E. / Nakuci, E. / Castro, J. / Chen, C.R. / Chan, T.C. / France, D.S. / Ashwell, M.A.
CitationJournal: J.Biol.Chem. / Year: 2011
Title: A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor.
Authors: Eathiraj, S. / Palma, R. / Hirschi, M. / Volckova, E. / Nakuci, E. / Castro, J. / Chen, C.R. / Chan, T.C. / France, D.S. / Ashwell, M.A.
History
DepositionApr 12, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 19, 2011Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,94213
Polymers71,5302
Non-polymers1,41111
Water7,422412
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5197
Polymers35,7651
Non-polymers7546
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4236
Polymers35,7651
Non-polymers6585
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)105.794, 119.581, 63.311
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Fibroblast growth factor receptor 2 / / FGFR-2 / K-sam / Keratinocyte growth factor receptor


Mass: 35765.203 Da / Num. of mol.: 2 / Fragment: UNP residues 458-768
Source method: isolated from a genetically manipulated source
Details: Bicistronic co-expression with lambda phosphatase / Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2, BEK, KGFR, KSAM / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): Codon Plus BL21(DE3)-RILP
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3RH / (6S)-6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-amine


Mass: 273.332 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N3
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 412 / 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: 2.8 Å3/Da / Density % sol: 56.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 15% polyethylene glycol 4000 and 0.3M lithium sulfate and 100 mM HEPES, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 17, 2008
RadiationMonochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 46498 / % possible obs: 97.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.908 / SU B: 4.567 / SU ML: 0.124 / Cross valid method: THROUGHOUT / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24746 2356 5.1 %RANDOM
Rwork0.2143 ---
obs0.21597 44033 97.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.603 Å2
Baniso -1Baniso -2Baniso -3
1--0.75 Å20 Å20 Å2
2---0.15 Å20 Å2
3---0.9 Å2
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4469 0 87 412 4968
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224652
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0081.9936311
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1855563
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.26524.129201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.80315800
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9391530
X-RAY DIFFRACTIONr_chiral_restr0.0710.2691
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023476
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1670.22234
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.2990.23171
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1270.2321
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1590.228
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0930.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5491.52939
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.91624562
X-RAY DIFFRACTIONr_scbond_it1.23231995
X-RAY DIFFRACTIONr_scangle_it1.9314.51749
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.156 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 168 -
Rwork0.253 3007 -
obs--92.65 %

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