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- PDB-6pnx: Crystal Structure of an Asymmetric Dimer of FGF Receptor 3 Kinase... -

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Basic information

Entry
Database: PDB / ID: 6pnx
TitleCrystal Structure of an Asymmetric Dimer of FGF Receptor 3 Kinases Trapped in A-loop Tyrosine Transphosphorylation Reaction
ComponentsFibroblast growth factor receptor 3
KeywordsTRANSFERASE / Tyrosine kinase / Transphosphorylation / Asymmetric dimer
Function / homology
Function and homology information


t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / chondrocyte proliferation / endochondral bone growth / FGFR3b ligand binding and activation / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation ...t(4;14) translocations of FGFR3 / negative regulation of developmental growth / fibroblast growth factor receptor apoptotic signaling pathway / Signaling by FGFR3 fusions in cancer / bone maturation / chondrocyte proliferation / endochondral bone growth / FGFR3b ligand binding and activation / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / Phospholipase C-mediated cascade; FGFR3 / endochondral ossification / positive regulation of phospholipase activity / bone morphogenesis / positive regulation of tyrosine phosphorylation of STAT protein / PI-3K cascade:FGFR3 / bone mineralization / fibroblast growth factor binding / PI3K Cascade / fibroblast growth factor receptor signaling pathway / cell surface receptor signaling pathway via JAK-STAT / chondrocyte differentiation / SHC-mediated cascade:FGFR3 / FRS-mediated FGFR3 signaling / transport vesicle / Signaling by FGFR3 in disease / skeletal system development / Negative regulation of FGFR3 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 / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / PIP3 activates AKT signaling / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / RAF/MAP kinase cascade / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of cell population proliferation / Golgi apparatus / cell surface / endoplasmic reticulum / extracellular region / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Fibroblast growth factor receptor 3 transmembrane domain / 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 ...Fibroblast growth factor receptor 3 transmembrane domain / 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 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.199 Å
AuthorsMohammadi, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)R01 DE13686 United States
CitationJournal: Nat.Chem.Biol. / Year: 2020
Title: Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.
Authors: Chen, L. / Marsiglia, W.M. / Chen, H. / Katigbak, J. / Erdjument-Bromage, H. / Kemble, D.J. / Fu, L. / Ma, J. / Sun, G. / Zhang, Y. / Liang, G. / Neubert, T.A. / Li, X. / Traaseth, N.J. / Mohammadi, M.
History
DepositionJul 3, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2020Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 4, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 3
B: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,2906
Polymers73,0882
Non-polymers1,2034
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: NMR spectroscopy, Cell-based assays
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4330 Å2
ΔGint-45 kcal/mol
Surface area29260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.686, 93.253, 75.490
Angle α, β, γ (deg.)90.000, 103.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Fibroblast growth factor receptor 3 / FGFR-3


Mass: 36543.855 Da / Num. of mol.: 2 / Mutation: C482A, C582S, R669E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR3, JTK4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P22607, 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.: 2 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.57 Å3/Da / Density % sol: 56.68 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Hepes, pH 7.5, and 1.8 M (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Aug 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.199→48.58 Å / Num. obs: 73565 / % possible obs: 99.6 % / Redundancy: 4.6 % / Rrim(I) all: 0.076 / Net I/σ(I): 14
Reflection shellResolution: 2.199→2.33 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 5907 / Rrim(I) all: 1.03 / % possible all: 98.5

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Processing

Software
NameVersionClassification
XDSdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4K33

4k33


Resolution: 2.199→39.378 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 24.51
RfactorNum. reflection% reflection
Rfree0.2299 3919 5.33 %
Rwork0.1928 --
obs0.1947 73565 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 242.12 Å2 / Biso mean: 74.7675 Å2 / Biso min: 28.89 Å2
Refinement stepCycle: final / Resolution: 2.199→39.378 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4625 0 72 249 4946
Biso mean--138.62 64.78 -
Num. residues----585
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.1992-2.22610.33041350.3234236694
2.2261-2.25420.31211340.3217242198
2.2542-2.28390.32941450.3431251899
2.2839-2.31520.34621390.31212459100
2.3152-2.34830.30821400.27942543100
2.3483-2.38330.27831400.27522437100
2.3833-2.42050.2591420.26132502100
2.4205-2.46020.24261430.26112508100
2.4602-2.50260.30861390.25932508100
2.5026-2.54810.31321390.25412453100
2.5481-2.59710.26321440.25322559100
2.5971-2.65010.26921400.23512477100
2.6501-2.70770.2221430.22142496100
2.7077-2.77070.2861380.22342470100
2.7707-2.840.27321420.22482525100
2.84-2.91670.27431380.22482504100
2.9167-3.00250.26581380.21492505100
3.0025-3.09940.21821400.21352480100
3.0994-3.21020.261400.21052495100
3.2102-3.33860.27221390.2082486100
3.3386-3.49050.24161390.19432489100
3.4905-3.67440.28291410.18472497100
3.6744-3.90440.19651420.17062497100
3.9044-4.20550.18561390.15712501100
4.2055-4.62820.17981400.1482497100
4.6282-5.29650.20521390.15412468100
5.2965-6.66780.19061410.17152498100
6.6678-39.37420.18061400.1461248799
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)
11.2022-0.96910.39043.8654-1.34281.76970.23190.2440.0027-0.1676-0.10010.2134-0.1915-0.3528-0.08360.37740.11850.00870.478-0.00780.28834.7953-20.4749-20.112
22.26232.7220.37984.98320.76840.86970.3689-0.32620.13830.6833-0.41780.20160.1614-0.16830.03230.4787-0.11850.01350.4892-0.01980.339216.064-17.249816.4543
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain 'A' and resid 456 through 757)A456 - 757
2X-RAY DIFFRACTION2(chain 'B' and resid 455 through 756)B455 - 756

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