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- PDB-5eg3: Crystal Structure of the Activated FGF Receptor 2 (FGFR2) Kinase ... -

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Basic information

Entry
Database: PDB / ID: 5eg3
TitleCrystal Structure of the Activated FGF Receptor 2 (FGFR2) Kinase Domain in complex with the cSH2 domain of Phospholipase C gamma (PLCgamma)
Components
  • 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1
  • Fibroblast growth factor receptor 2
KeywordsTransferase/Hydrolase / Signaling Complex / Tyrosine Kinase domain / SH2 domain / Recruitment / Phosphorylation / Transferase-Hydrolase complex
Function / homology
Function and homology information


PECAM1 interactions / EGFR interacts with phospholipase C-gamma / Activated NTRK2 signals through PLCG1 / Activated NTRK3 signals through PLCG1 / phosphatidylinositol catabolic process / Phospholipase C-mediated cascade: FGFR1 / Phospholipase C-mediated cascade; FGFR3 / Phospholipase C-mediated cascade; FGFR4 / FCERI mediated Ca+2 mobilization / ISG15 antiviral mechanism ...PECAM1 interactions / EGFR interacts with phospholipase C-gamma / Activated NTRK2 signals through PLCG1 / Activated NTRK3 signals through PLCG1 / phosphatidylinositol catabolic process / Phospholipase C-mediated cascade: FGFR1 / Phospholipase C-mediated cascade; FGFR3 / Phospholipase C-mediated cascade; FGFR4 / FCERI mediated Ca+2 mobilization / ISG15 antiviral mechanism / Generation of second messenger molecules / Phospholipase C-mediated cascade; FGFR2 / Downstream signal transduction / Signaling by ALK / Role of phospholipids in phagocytosis / inositol trisphosphate biosynthetic process / DAP12 signaling / VEGFR2 mediated cell proliferation / calcium-dependent phospholipase C activity / Synthesis of IP3 and IP4 in the cytosol / RET signaling / inositol trisphosphate metabolic process / response to curcumin / 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 / phosphoinositide phospholipase C / FCERI mediated MAPK activation / 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 / pyramidal neuron development / response to gravity / positive regulation of epithelial cell proliferation involved in lung morphogenesis / 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 / phosphatidylinositol metabolic process / 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 / phosphatidylinositol phospholipase C activity / embryonic pattern specification / outflow tract septum morphogenesis / COP9 signalosome / phospholipase C activity / positive regulation of phospholipase activity / neurotrophin TRKA receptor binding / lung-associated mesenchyme development / mesodermal cell differentiation / digestive tract development / positive regulation of endothelial cell apoptotic process / embryonic cranial skeleton morphogenesis / regulation of smoothened signaling pathway / phosphatidylinositol-mediated signaling / bone morphogenesis / skeletal system morphogenesis / odontogenesis / ureteric bud development / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / clathrin-coated vesicle / regulation of osteoblast differentiation / ventricular cardiac muscle tissue morphogenesis / inner ear morphogenesis / Signaling by FGFR2 IIIa TM / organ growth / midbrain development / hair follicle morphogenesis
Similarity search - Function
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1, SH3 domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma / PLC-gamma, C-terminal SH2 domain / PLC-gamma, N-terminal SH2 domain / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain / Phosphatidylinositol-specific phospholipase C, Y domain / Phosphatidylinositol-specific phospholipase Y-box domain profile. / Phospholipase C, catalytic domain (part); domain Y / Phosphatidylinositol-specific phospholipase X-box domain profile. ...1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1, SH3 domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma / PLC-gamma, C-terminal SH2 domain / PLC-gamma, N-terminal SH2 domain / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain / Phosphatidylinositol-specific phospholipase C, Y domain / Phosphatidylinositol-specific phospholipase Y-box domain profile. / Phospholipase C, catalytic domain (part); domain Y / Phosphatidylinositol-specific phospholipase X-box domain profile. / Phosphatidylinositol-specific phospholipase C, X domain / Phosphatidylinositol-specific phospholipase C, X domain / Phospholipase C, catalytic domain (part); domain X / PLC-like phosphodiesterase, TIM beta/alpha-barrel domain superfamily / Fibroblast growth factor receptor family / SH2 domain / C2 domain / Protein kinase C conserved region 2 (CalB) / SHC Adaptor Protein / C2 domain / C2 domain profile. / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / PH domain / C2 domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Src homology 3 domains / SH2 domain / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / SH2 domain superfamily / EF-hand calcium-binding domain profile. / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / EF-hand domain / EF-hand domain pair / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / PH-like domain superfamily / 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 / 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.606 Å
AuthorsHuang, Z. / Li, X. / Mohammadi, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)DE13686 United States
CitationJournal: Mol.Cell / Year: 2016
Title: Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase C gamma.
Authors: Huang, Z. / Marsiglia, W.M. / Basu Roy, U. / Rahimi, N. / Ilghari, D. / Wang, H. / Chen, H. / Gai, W. / Blais, S. / Neubert, T.A. / Mansukhani, A. / Traaseth, N.J. / Li, X. / Mohammadi, M.
History
DepositionOct 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Structure summary
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 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_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,0205
Polymers51,4662
Non-polymers5543
Water99155
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-29 kcal/mol
Surface area21490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.609, 53.231, 127.660
Angle α, β, γ (deg.)90.00, 100.11, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 38155.676 Da / Num. of mol.: 1 / Fragment: UNP residues 458-778
Mutation: Y466F, C491A, E565A, Y586L, Y588P, Y656F, Y657F, K659E
Source method: isolated from a genetically manipulated source
Details: Tyr326 is phosphorylated / Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2, BEK, KGFR, KSAM / Production host: Escherichia coli (E. coli)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Protein 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 / Phosphoinositide phospholipase C-gamma-1 / Phospholipase C-gamma-1 / PLC-gamma-1


Mass: 13310.129 Da / Num. of mol.: 1 / Fragment: UNP residues 661-773
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Plcg1 / Production host: Escherichia coli (E. coli)
References: UniProt: P10686, phosphoinositide phospholipase C
#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: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 2.59 Å3/Da / Density % sol: 52.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 25 mM HEPES (pH 7.5), PEG20000 (12% 18%) and 2% (w/v) Benzamidine hydrochloride

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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: Jul 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97907 Å / Relative weight: 1
ReflectionResolution: 2.6→37.859 Å / Num. obs: 15981 / % possible obs: 98.2 % / Redundancy: 6.6 % / Rsym value: 0.093 / Net I/σ(I): 27.9
Reflection shellResolution: 2.6→2.64 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.256 / Mean I/σ(I) obs: 5.9 / % possible all: 93.5

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PVY, 2PLE

2pvy

2ple


Resolution: 2.606→37.859 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 1597 10 %Random selection
Rwork0.1854 ---
obs0.1907 15973 97.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.606→37.859 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3326 0 33 55 3414
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093430
X-RAY DIFFRACTIONf_angle_d1.214640
X-RAY DIFFRACTIONf_dihedral_angle_d13.7041312
X-RAY DIFFRACTIONf_chiral_restr0.044499
X-RAY DIFFRACTIONf_plane_restr0.005596
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6055-2.68960.30981330.23851200X-RAY DIFFRACTION90
2.6896-2.78570.30841450.24191298X-RAY DIFFRACTION97
2.7857-2.89720.30981390.24521256X-RAY DIFFRACTION96
2.8972-3.0290.3381430.2381291X-RAY DIFFRACTION96
3.029-3.18860.27241460.22661302X-RAY DIFFRACTION97
3.1886-3.38830.27541430.20561290X-RAY DIFFRACTION98
3.3883-3.64970.25011480.191327X-RAY DIFFRACTION99
3.6497-4.01660.22961480.16281338X-RAY DIFFRACTION100
4.0166-4.59690.17241480.14231326X-RAY DIFFRACTION100
4.5969-5.78830.19491510.15721365X-RAY DIFFRACTION100
5.7883-37.86320.18061530.15321383X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 21.3631 Å / Origin y: 9.0993 Å / Origin z: 28.3348 Å
111213212223313233
T0.1988 Å20.0079 Å20.006 Å2-0.1981 Å2-0.0287 Å2--0.173 Å2
L0.6906 °2-0.3413 °20.1472 °2-1.1122 °2-0.3901 °2--0.3941 °2
S-0.0904 Å °-0.1781 Å °-0.0085 Å °0.1741 Å °0.0963 Å °0.0416 Å °-0.0533 Å °-0.0516 Å °-0.007 Å °
Refinement TLS groupSelection details: all

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