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

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Basic information

Entry
Database: PDB / ID: 5uhn
TitleCrystal Structure of the Tyrosine Kinase Domain of FGF Receptor 2 harboring a N549H/E565A Double Gain-of-Function Mutation
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / Tyrosine Kinase Domain Gain-of-Function ATP Analog Cell Surface Receptor
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 / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell differentiation / branching involved in labyrinthine layer morphogenesis / pyramidal neuron development / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland 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 / 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 / ventricular cardiac muscle tissue morphogenesis / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / 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 / negative regulation of keratinocyte proliferation / fibroblast growth factor receptor signaling pathway / epithelial to mesenchymal transition / 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 / post-embryonic development / positive regulation of epithelial cell proliferation / animal organ morphogenesis / lung development / Negative regulation of FGFR2 signaling / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Phosphorylase Kinase; domain 1 / 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: 2.909 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 11, 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.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

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)75,4048
Polymers74,1532
Non-polymers1,2516
Water362
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7024
Polymers37,0771
Non-polymers6263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7024
Polymers37,0771
Non-polymers6263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.334, 78.557, 116.546
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: 37076.590 Da / Num. of mol.: 2 / Fragment: UNP residues 342-652 / Mutation: N549H, E565A
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.: 2 / 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.: 2 / 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: 2.08 Å3/Da / Density % sol: 40.82 %
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: 0.97885 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Sep 24, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97885 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 14079 / % possible obs: 100 % / Redundancy: 14 % / Net I/σ(I): 26.5
Reflection shellResolution: 2.9→2.95 Å / Redundancy: 12.6 % / Mean I/σ(I) obs: 7.2 / Rsym value: 0.363 / % possible all: 100

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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: 2.909→39.279 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 35.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3112 1398 10.01 %
Rwork0.2541 --
obs0.2597 13962 98.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.909→39.279 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4323 0 74 2 4399
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024494
X-RAY DIFFRACTIONf_angle_d0.4676095
X-RAY DIFFRACTIONf_dihedral_angle_d11.1122729
X-RAY DIFFRACTIONf_chiral_restr0.04678
X-RAY DIFFRACTIONf_plane_restr0.004764
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9089-3.01290.35791300.32461168X-RAY DIFFRACTION93
3.0129-3.13340.35531380.28531229X-RAY DIFFRACTION99
3.1334-3.2760.3551390.271244X-RAY DIFFRACTION100
3.276-3.44860.3291380.28171252X-RAY DIFFRACTION99
3.4486-3.66450.2881350.24371228X-RAY DIFFRACTION100
3.6645-3.94720.31721420.23181277X-RAY DIFFRACTION100
3.9472-4.3440.28861390.23211265X-RAY DIFFRACTION100
4.344-4.97150.28261410.22791268X-RAY DIFFRACTION100
4.9715-6.25950.31551440.25621287X-RAY DIFFRACTION99
6.2595-39.28210.29671520.25961346X-RAY DIFFRACTION98
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)
10.4103-0.0288-0.28410.01430.01020.19890.31560.09240.0990.00740.074-0.049-0.0964-0.04540.11940.232-0.0157-0.040.22550.02360.19217.08637.6244.0752
20.4843-0.11640.05630.1793-0.17050.12950.04170.25050.1414-0.0695-0.0521-0.0187-0.05430.0463-0.02850.158-0.05780.00420.1135-0.00380.145417.234739.497613.5211
30.14370.01580.06850.0650.0370.2064-0.04760.0116-0.0732-0.1313-0.0842-0.0419-0.0990.0729-0.18190.20570.042-0.00480.1785-0.05480.192712.407737.179727.7154
40.02960.04750.1440.04030.15270.6019-0.0278-0.00030.0079-0.0703-0.0051-0.1277-0.207-0.0734-0.02890.0989-0.02440.06430.0755-0.00620.219524.464428.605631.8287
50.7001-0.038-0.06350.83180.02330.9168-0.1339-0.1714-0.01380.2071-0.06430.01950.3077-0.2955-0.38680.1197-0.02720.0050.1066-0.01090.070414.528634.29742.5489
60.0543-0.035-0.0020.05650.02550.03640.1009-0.1057-0.06630.1910.0338-0.17380.32140.11860.08850.20270.0208-0.0709-0.0044-0.15480.226250.145337.520731.2566
71.01380.16710.07120.20890.19760.18570.2879-0.1579-0.1064-0.0233-0.1247-0.0452-0.1224-0.00910.23070.14570.0840.01660.0929-0.0670.119750.136638.957922.3095
80.0827-0.04150.07110.03490.01350.1089-0.0751-0.0481-0.1724-0.0787-0.0356-0.16420.06590.0926-0.02530.17240.00480.04350.17270.01120.203754.854337.95367.7656
90.08190.01190.11390.00540.01950.15230.0280.006-0.01070.03780.03790.05510.0211-0.03570.16370.24170.3670.10950.24540.00680.204745.713227.355313.1589
100.04330.00750.00210.0088-0.01670.09650.05890.1094-0.01230.18910.15530.2316-0.0091-0.04140.07840.21540.06680.01290.10920.02360.195345.002229.48831.0038
110.0098-0.00640.0180.003-0.01010.02210.05020.11060.1537-0.09670.12350.07330.1017-0.18880.00050.35470.09480.03180.39720.04520.308935.143934.6122-3.1538
120.42320.0484-0.09950.39440.09830.2439-0.13840.1156-0.1362-0.2672-0.0794-0.03650.27650.1318-0.2320.25370.08520.03120.45140.01960.176452.904434.5558-7.2189
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 469 through 493 )
2X-RAY DIFFRACTION2chain 'A' and (resid 494 through 599 )
3X-RAY DIFFRACTION3chain 'A' and (resid 600 through 639 )
4X-RAY DIFFRACTION4chain 'A' and (resid 640 through 717 )
5X-RAY DIFFRACTION5chain 'A' and (resid 718 through 764 )
6X-RAY DIFFRACTION6chain 'B' and (resid 469 through 493 )
7X-RAY DIFFRACTION7chain 'B' and (resid 494 through 599 )
8X-RAY DIFFRACTION8chain 'B' and (resid 600 through 642 )
9X-RAY DIFFRACTION9chain 'B' and (resid 643 through 666 )
10X-RAY DIFFRACTION10chain 'B' and (resid 667 through 697 )
11X-RAY DIFFRACTION11chain 'B' and (resid 698 through 717 )
12X-RAY DIFFRACTION12chain 'B' and (resid 718 through 764 )

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