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- PDB-5ugx: Crystal Structure of the Tyrosine Kinase Domain of FGF Receptor 2... -

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Basic information

Entry
Database: PDB / ID: 5ugx
TitleCrystal Structure of the Tyrosine Kinase Domain of FGF Receptor 2 Harboring a E565A/D650V double Gain-of-Function Mutation
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / Tyrosine Kinase Domain / Gain-of-Function Mutations / Cell Surface ATP Analog
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 / FRS-mediated FGFR2 signaling / cellular response to retinoic acid / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / 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: 2.349 Å
AuthorsMohammadi, M. / Chen, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)DE13686 United States
CitationJournal: Elife / Year: 2017
Title: Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.
Authors: Chen, H. / Marsiglia, W.M. / Cho, M.K. / Huang, Z. / Deng, J. / Blais, S.P. / Gai, W. / Bhattacharya, S. / Neubert, T.A. / Traaseth, N.J. / Mohammadi, M.
History
DepositionJan 10, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)75,51610
Polymers74,0732
Non-polymers1,4438
Water68538
1
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7585
Polymers37,0371
Non-polymers7224
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7585
Polymers37,0371
Non-polymers7224
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.973, 77.860, 115.809
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 37036.586 Da / Num. of mol.: 2 / Fragment: UNP residues 341-651 / Mutation: E565A, D650V
Source method: isolated from a genetically manipulated source
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: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / 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.: 2 / 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


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.04 Å3/Da / Density % sol: 39.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 25 mM HEPES (pH 7.5), 15%-25% w/v PEG 4000, 0.2-0.3 M Ammonium sulfate

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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: 2.35→50 Å / Num. obs: 25875 / % possible obs: 99.8 % / Redundancy: 14.2 % / Rsym value: 0.087 / Net I/σ(I): 42.3
Reflection shellResolution: 2.35→2.39 Å / Redundancy: 11.6 % / Mean I/σ(I) obs: 9.5 / Rsym value: 0.255 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PSQ

2psq


Resolution: 2.349→38.176 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2749 1994 7.74 %
Rwork0.2151 --
obs0.2197 25765 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.349→38.176 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4562 0 84 38 4684
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094750
X-RAY DIFFRACTIONf_angle_d1.1096447
X-RAY DIFFRACTIONf_dihedral_angle_d9.0714037
X-RAY DIFFRACTIONf_chiral_restr0.058710
X-RAY DIFFRACTIONf_plane_restr0.007815
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3492-2.40790.33051360.24811608X-RAY DIFFRACTION97
2.4079-2.4730.27171400.23541677X-RAY DIFFRACTION99
2.473-2.54580.25491400.23371659X-RAY DIFFRACTION100
2.5458-2.62790.29951410.23691698X-RAY DIFFRACTION100
2.6279-2.72180.28061390.24511671X-RAY DIFFRACTION100
2.7218-2.83080.35111410.24221677X-RAY DIFFRACTION100
2.8308-2.95960.31251420.25291685X-RAY DIFFRACTION100
2.9596-3.11550.29681420.23871707X-RAY DIFFRACTION100
3.1155-3.31060.28331430.23071693X-RAY DIFFRACTION100
3.3106-3.56610.29821410.21441696X-RAY DIFFRACTION100
3.5661-3.92460.23691440.20231717X-RAY DIFFRACTION100
3.9246-4.49180.2611450.17671725X-RAY DIFFRACTION100
4.4918-5.65620.23921460.19021739X-RAY DIFFRACTION100
5.6562-38.1810.25231540.19851819X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.9324-0.6110.40821.39330.1881.10180.0916-0.0810.04080.06320.0145-0.05350.14230.070.00020.1666-0.0048-0.01640.14390.01790.165252.919938.976930.6647
20.74040.58330.63710.63190.20781.06780.14360.1066-0.0651-0.0211-0.14290.0470.0450.12750.00190.11320.0517-0.01380.13910.00390.172248.274332.654525.0457
30.55540.4359-0.3010.57590.18521.20160.046-0.0158-0.0155-0.0725-0.0997-0.1921-0.07430.3588-0.00680.1641-0.02290.00270.1610.00270.102751.991745.26387.5311
41.08420.0941-0.24920.1369-0.39251.063-0.01720.007-0.1283-0.0445-0.03960.01220.0810.088100.19610.01920.01120.20260.00950.206444.115432.28924.2776
50.43240.2573-0.54250.4745-0.15950.8655-0.26840.0909-0.159-0.24960.0337-0.06640.37920.1096-0.00440.30.00550.05070.3702-0.0150.186252.418434.2077-7.2782
60.6466-0.41530.08251.05190.47850.9079-0.03930.1730.07050.0097-0.08120.0365-0.2197-0.20870.00010.2443-0.0443-0.01560.2880.03840.216114.279439.29164.8505
70.541-0.3821-0.50860.6443-0.05160.91670.07350.1227-0.0027-0.0736-0.0358-0.07060.00130.022700.2014-0.0376-0.04290.2121-0.00160.198118.595936.503813.495
80.07430.12870.03280.2290.0780.07880.30390.08010.3709-0.0976-0.02740.0146-0.07260.134400.5211-0.00910.01860.3301-0.06360.440321.562555.141931.3704
90.6339-0.57780.22550.595-0.44420.6652-0.01870.10470.1129-0.09760.0429-0.0701-0.1613-0.20750.00090.13870.0084-0.00620.1178-0.03120.197413.91832.90126.6401
101.01210.41540.66290.7075-0.28240.96040.0202-0.1779-0.19690.11030.08970.03380.01360.23720.01290.146-0.02780.00390.1205-0.01130.165526.545429.286734.332
110.4379-0.2878-0.23130.334-0.22230.9204-0.0764-0.2471-0.09990.08970.02060.1181-0.2039-0.0646-0.00040.1712-0.0001-0.02250.1842-0.00530.201314.430633.640342.591
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 468 through 510 )
2X-RAY DIFFRACTION2chain 'B' and (resid 511 through 560 )
3X-RAY DIFFRACTION3chain 'B' and (resid 561 through 620 )
4X-RAY DIFFRACTION4chain 'B' and (resid 621 through 717 )
5X-RAY DIFFRACTION5chain 'B' and (resid 718 through 764 )
6X-RAY DIFFRACTION6chain 'A' and (resid 468 through 510 )
7X-RAY DIFFRACTION7chain 'A' and (resid 511 through 579 )
8X-RAY DIFFRACTION8chain 'A' and (resid 580 through 599 )
9X-RAY DIFFRACTION9chain 'A' and (resid 600 through 657 )
10X-RAY DIFFRACTION10chain 'A' and (resid 658 through 717 )
11X-RAY DIFFRACTION11chain 'A' and (resid 718 through 764 )

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