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- PDB-4j96: Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harbori... -

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Basic information

Entry
Database: PDB / ID: 4j96
TitleCrystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harboring the Pathogenic Gain-of-Function K659M Mutation Identified in Cervical Cancer.
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / Kinase Domain Fold Consisting of N- and C-lobes / Receptor Tyrosine Kinase / ATP Binding
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 / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / 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 / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / mesenchymal cell differentiation / positive regulation of phospholipase activity / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / branching involved in labyrinthine layer morphogenesis / lung lobe morphogenesis / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / embryonic pattern specification / pyramidal neuron development / embryonic cranial skeleton morphogenesis / lung-associated mesenchyme development / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / bone morphogenesis / digestive tract development / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / skeletal system morphogenesis / organ growth / hair follicle morphogenesis / inner ear morphogenesis / Signaling by FGFR2 IIIa TM / lung alveolus development / regulation of osteoblast differentiation / ventricular cardiac muscle tissue morphogenesis / PI-3K cascade:FGFR2 / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / midbrain development / bone mineralization / fibroblast growth factor binding / positive regulation of cell division / PI3K Cascade / epithelial to mesenchymal transition / excitatory synapse / fibroblast growth factor receptor signaling pathway / positive regulation of Wnt signaling pathway / cell fate commitment / negative regulation of keratinocyte proliferation / embryonic organ development / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of cell cycle / cellular response to retinoic acid / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / lung development / peptidyl-tyrosine phosphorylation / animal organ morphogenesis / positive regulation of epithelial cell proliferation / post-embryonic development / Negative regulation of FGFR2 signaling / receptor protein-tyrosine kinase / bone development / Constitutive Signaling by Aberrant PI3K in Cancer
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. ...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 / 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
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / CITRATE ANION / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2972 Å
AuthorsChen, H. / Mohammadi, M.
CitationJournal: Cell Rep / Year: 2013
Title: Cracking the Molecular Origin of Intrinsic Tyrosine Kinase Activity through Analysis of Pathogenic Gain-of-Function Mutations.
Authors: Chen, H. / Huang, Z. / Dutta, K. / Blais, S. / Neubert, T.A. / Li, X. / Cowburn, D. / Traaseth, N.J. / Mohammadi, M.
History
DepositionFeb 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2013Group: Database references
Revision 1.2Dec 28, 2016Group: Structure summary
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 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4219
Polymers74,2252
Non-polymers1,1967
Water3,297183
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3983
Polymers37,1131
Non-polymers2852
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0236
Polymers37,1131
Non-polymers9115
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3230 Å2
ΔGint-15 kcal/mol
Surface area27310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.852, 73.852, 310.716
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number95
Space group name H-MP4322

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 37112.598 Da / Num. of mol.: 2
Fragment: Human FGF Receptor 2 Kinase Domain (UNP Residues 458-768)
Mutation: C491A, K659M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BEK, FGFR2, KGFR, KSAM / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLys-S
References: UniProt: P21802, receptor protein-tyrosine kinase

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Non-polymers , 5 types, 190 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H5O7
#4: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 183 / 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: 2.85 Å3/Da / Density % sol: 56.9 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100mM HEPES pH7.5, 25% PEG 4000, 200mM (NH4)2SO4, 100mM HOC(COONa)(CH2COONa)2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4C / Wavelength: 0.97907 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Dec 8, 2011
RadiationMonochromator: Single crystal bender / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97907 Å / Relative weight: 1
ReflectionResolution: 2.297→50 Å / Num. all: 39689 / Num. obs: 39610 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 25.9 % / Rsym value: 0.114 / Net I/σ(I): 43.6
Reflection shellResolution: 2.297→2.34 Å / Redundancy: 21.4 % / Mean I/σ(I) obs: 4.4 / Rsym value: 0.498 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
PHENIX(phenix.refine: 1.8.1_1168)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2PVY

2pvy


Resolution: 2.2972→47.549 Å / SU ML: 0.24 / σ(F): 1.33 / Phase error: 21.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2188 1994 5.04 %
Rwork0.1762 --
obs0.1784 39541 99.67 %
all-39689 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2972→47.549 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4815 0 73 183 5071
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0135020
X-RAY DIFFRACTIONf_angle_d1.3996818
X-RAY DIFFRACTIONf_dihedral_angle_d14.8361930
X-RAY DIFFRACTIONf_chiral_restr0.083743
X-RAY DIFFRACTIONf_plane_restr0.007877
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2972-2.35460.31011390.21782619X-RAY DIFFRACTION100
2.3546-2.41830.22271400.19672610X-RAY DIFFRACTION100
2.4183-2.48950.2491390.18232644X-RAY DIFFRACTION100
2.4895-2.56980.23191400.18122631X-RAY DIFFRACTION100
2.5698-2.66160.22251410.19172646X-RAY DIFFRACTION100
2.6616-2.76820.23781400.19852639X-RAY DIFFRACTION100
2.7682-2.89420.26481420.20422649X-RAY DIFFRACTION100
2.8942-3.04670.24981400.20382650X-RAY DIFFRACTION100
3.0467-3.23760.24021410.20242691X-RAY DIFFRACTION100
3.2376-3.48750.23451430.18642686X-RAY DIFFRACTION100
3.4875-3.83830.23371420.16422674X-RAY DIFFRACTION99
3.8383-4.39340.18211450.14652723X-RAY DIFFRACTION100
4.3934-5.53390.18061480.15492773X-RAY DIFFRACTION100
5.5339-47.55940.20791540.1752912X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 40.5622 Å / Origin y: 16.6883 Å / Origin z: 20.9226 Å
111213212223313233
T0.2377 Å20.0313 Å20.0101 Å2-0.2068 Å20.0063 Å2--0.1555 Å2
L1.9871 °20.1321 °2-0.3046 °2-0.414 °20.0685 °2--0.7413 °2
S-0.0343 Å °0.0366 Å °0.0626 Å °-0.0252 Å °0.0186 Å °-0.0743 Å °0.0341 Å °0.0899 Å °0.0147 Å °
Refinement TLS groupSelection details: all

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