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- PDB-4j98: Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harbori... -

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Basic information

Entry
Database: PDB / ID: 4j98
TitleCrystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harboring the Gain-of-Function K659Q Mutation.
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / FGF Receptor / Receptor Tyrosine Kinase / Gain-of-function Mutation / 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 / lung lobe 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 / epithelial cell proliferation involved in salivary gland morphogenesis / branching involved in labyrinthine layer morphogenesis / mesenchymal cell proliferation involved in lung development / pyramidal neuron development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / branching involved in salivary gland morphogenesis / embryonic pattern specification / positive regulation of phospholipase activity / lung-associated mesenchyme development / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / mesodermal cell differentiation / bone morphogenesis / digestive tract development / skeletal system morphogenesis / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / inner ear morphogenesis / organ growth / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / ventricular cardiac muscle tissue morphogenesis / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / lung alveolus development / prostate epithelial cord elongation / midbrain development / bone mineralization / fibroblast growth factor binding / positive regulation of cell division / excitatory synapse / PI3K Cascade / positive regulation of Wnt signaling pathway / cell fate commitment / fibroblast growth factor receptor signaling pathway / epithelial to mesenchymal transition / negative regulation of keratinocyte proliferation / embryonic organ development / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / cellular response to transforming growth factor beta stimulus / cellular response to retinoic acid / FRS-mediated FGFR2 signaling / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / positive regulation of epithelial cell proliferation / post-embryonic development / animal organ morphogenesis / Negative regulation of FGFR2 signaling / lung development / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity
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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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: 2.3067 Å
AuthorsHuang, Z. / Chen, 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

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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)75,2058
Polymers74,2192
Non-polymers9866
Water4,143230
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3023
Polymers37,1101
Non-polymers1922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9035
Polymers37,1101
Non-polymers7934
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3210 Å2
ΔGint-13 kcal/mol
Surface area27390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.785, 73.785, 313.749
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number95
Space group name H-MP4322

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Components

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


Mass: 37109.531 Da / Num. of mol.: 2
Fragment: Human FGF Receptor 2 Kinase Domain (UNP Residues 458-768)
Mutation: C491A, K659Q
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.88 Å3/Da / Density % sol: 57.24 %
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: X4A / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Jul 20, 2012
RadiationMonochromator: KOHZU double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 39499 / Num. obs: 38198 / % possible obs: 96.6 % / Redundancy: 6.8 % / Rsym value: 0.118 / Net I/σ(I): 33.6
Reflection shellResolution: 2.3→2.34 Å / Redundancy: 7.7 % / Mean I/σ(I) obs: 8.9 / Rsym value: 0.355 / % possible all: 99.8

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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: 2.3067→43.441 Å / SU ML: 0.22 / σ(F): 1.33 / Phase error: 21.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2345 2000 5.24 %
Rwork0.1871 --
obs0.1896 38193 96.71 %
all-38222 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3067→43.441 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4818 0 56 230 5104
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084992
X-RAY DIFFRACTIONf_angle_d1.1626776
X-RAY DIFFRACTIONf_dihedral_angle_d15.0141892
X-RAY DIFFRACTIONf_chiral_restr0.076739
X-RAY DIFFRACTIONf_plane_restr0.005868
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3067-2.36440.29011420.20352580X-RAY DIFFRACTION99
2.3644-2.42830.27611440.20282608X-RAY DIFFRACTION100
2.4283-2.49980.26071450.18782611X-RAY DIFFRACTION100
2.4998-2.58040.22341440.18812615X-RAY DIFFRACTION100
2.5804-2.67270.27731450.18952608X-RAY DIFFRACTION100
2.6727-2.77970.27491450.19272630X-RAY DIFFRACTION100
2.7797-2.90610.26681440.20112615X-RAY DIFFRACTION99
2.9061-3.05930.23551460.1992641X-RAY DIFFRACTION99
3.0593-3.25090.2461450.20592618X-RAY DIFFRACTION99
3.2509-3.50180.22361440.19332608X-RAY DIFFRACTION97
3.5018-3.8540.22991390.18212510X-RAY DIFFRACTION94
3.854-4.41130.21541310.17292385X-RAY DIFFRACTION88
4.4113-5.55590.19261400.16692515X-RAY DIFFRACTION91
5.5559-43.4490.22421460.18242649X-RAY DIFFRACTION90
Refinement TLS params.Method: refined / Origin x: 40.6993 Å / Origin y: 16.908 Å / Origin z: 21.135 Å
111213212223313233
T0.1648 Å20.0225 Å20.0069 Å2-0.1597 Å20.0151 Å2--0.131 Å2
L1.5165 °20.1063 °2-0.0739 °2-0.3371 °20.0212 °2--0.489 °2
S-0.0093 Å °0.0496 Å °0.0526 Å °-0.0106 Å °0.0037 Å °-0.0462 Å °0.0227 Å °0.0598 Å °0.0033 Å °
Refinement TLS groupSelection details: all

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