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- PDB-4j95: Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harbori... -

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Basic information

Entry
Database: PDB / ID: 4j95
TitleCrystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harboring the Pathogenic K659N Mutation Responsible for an Unclassified Craniosynostosis Syndrome in Space Group C2.
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 / 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 / digestive tract development / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / bone morphogenesis / skeletal system morphogenesis / odontogenesis / ureteric bud development / positive regulation of mesenchymal cell proliferation / regulation of osteoblast differentiation / ventricular cardiac muscle tissue morphogenesis / inner ear morphogenesis / Signaling by FGFR2 IIIa TM / organ growth / midbrain development / hair follicle morphogenesis / lung alveolus development / fibroblast growth factor binding / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / 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 / epithelial to mesenchymal transition / negative regulation of keratinocyte proliferation / fibroblast growth factor receptor signaling pathway / embryonic organ development / cell fate commitment / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / FRS-mediated FGFR2 signaling / positive regulation of cardiac muscle cell proliferation / 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 / post-embryonic development / regulation of ERK1 and ERK2 cascade / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway
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 / 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
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3767 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
C: Fibroblast growth factor receptor 2
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)151,07515
Polymers148,3824
Non-polymers2,69311
Water1,928107
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7934
Polymers37,0961
Non-polymers6973
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,6973
Polymers37,0961
Non-polymers6012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8895
Polymers37,0961
Non-polymers7934
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,6973
Polymers37,0961
Non-polymers6012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4907
Polymers74,1912
Non-polymers1,2995
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint-62 kcal/mol
Surface area24350 Å2
MethodPISA
6
C: Fibroblast growth factor receptor 2
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5868
Polymers74,1912
Non-polymers1,3956
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4580 Å2
ΔGint-66 kcal/mol
Surface area24180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)278.634, 78.122, 72.791
Angle α, β, γ (deg.)90.00, 101.90, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-912-

HOH

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Components

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


Mass: 37095.504 Da / Num. of mol.: 4
Fragment: Human FGF Receptor 2 Kinase Domain (UNP Residues 458-768)
Mutation: C491A, K659N
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
#2: Chemical
ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100mM HEPES pH7.5, 25% PEG 4000, 200mM (NH4)2SO4, 3% v/v CH3CH2OH, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: SINGLE WAVELENGTH
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Sep 16, 2011
RadiationMonochromator: KOHZU DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.376→50 Å / Num. all: 95475 / Num. obs: 60839 / % possible obs: 99.4 % / Redundancy: 7.5 % / Rsym value: 0.059 / Net I/σ(I): 50.8
Reflection shellResolution: 2.376→2.44 Å / Redundancy: 7.6 % / Mean I/σ(I) obs: 7.8 / Rsym value: 0.417 / % possible all: 99.3

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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: 2.3767→37.55 Å / SU ML: 0.28 / σ(F): 1.34 / Phase error: 27.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2548 2005 3.3 %
Rwork0.2122 --
obs0.2137 60769 98.26 %
all-60839 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3767→37.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8770 0 159 107 9036
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049140
X-RAY DIFFRACTIONf_angle_d0.89712407
X-RAY DIFFRACTIONf_dihedral_angle_d13.9213445
X-RAY DIFFRACTIONf_chiral_restr0.0591375
X-RAY DIFFRACTIONf_plane_restr0.0041562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3767-2.43610.31351220.25213586X-RAY DIFFRACTION84
2.4361-2.50190.29331420.2524182X-RAY DIFFRACTION99
2.5019-2.57560.33141460.25954218X-RAY DIFFRACTION99
2.5756-2.65870.32551380.25064213X-RAY DIFFRACTION99
2.6587-2.75370.32491470.25134232X-RAY DIFFRACTION100
2.7537-2.86390.33821460.26374203X-RAY DIFFRACTION99
2.8639-2.99420.30451450.24864257X-RAY DIFFRACTION100
2.9942-3.15190.30091430.24354267X-RAY DIFFRACTION100
3.1519-3.34930.25631490.23714232X-RAY DIFFRACTION100
3.3493-3.60770.25131550.21614232X-RAY DIFFRACTION100
3.6077-3.97040.22361380.19584280X-RAY DIFFRACTION100
3.9704-4.54410.21551480.17444301X-RAY DIFFRACTION100
4.5441-5.72180.22881440.18094300X-RAY DIFFRACTION100
5.7218-37.55460.22191420.19844261X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: 32.4383 Å / Origin y: 20.3732 Å / Origin z: 14.0409 Å
111213212223313233
T0.3318 Å20.0033 Å20.0268 Å2-0.3415 Å20.0662 Å2--0.2966 Å2
L0.2098 °20.1997 °20.0082 °2-0.7643 °20.0401 °2--0.128 °2
S-0.0909 Å °0.0935 Å °0.0377 Å °-0.2994 Å °0.0739 Å °-0.1549 Å °-0.0415 Å °-0.0877 Å °0.0102 Å °
Refinement TLS groupSelection details: all

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