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- PDB-6lvm: Crystal structure of FGFR3 in complex with pyrimidine derivative -

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Basic information

Entry
Database: PDB / ID: 6lvm
TitleCrystal structure of FGFR3 in complex with pyrimidine derivative
ComponentsFibroblast growth factor receptor 3
KeywordsTRANSFERASE / protein kinase / SIGNALING PROTEIN
Function / homology
Function and homology information


fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / 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 ...fibroblast growth factor receptor apoptotic signaling pathway / t(4;14) translocations of FGFR3 / negative regulation of developmental growth / 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 / fibroblast growth factor receptor activity / endochondral ossification / positive regulation of phospholipase activity / bone morphogenesis / PI-3K cascade:FGFR3 / fibroblast growth factor binding / bone mineralization / cell surface receptor signaling pathway via JAK-STAT / PI3K Cascade / fibroblast growth factor receptor signaling pathway / chondrocyte differentiation / SHC-mediated cascade:FGFR3 / FRS-mediated FGFR3 signaling / positive regulation of tyrosine phosphorylation of STAT protein / transport vesicle / Signaling by FGFR3 in disease / skeletal system development / Negative regulation of FGFR3 signaling / cell surface receptor protein tyrosine kinase signaling pathway / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / MAPK cascade / PIP3 activates AKT signaling / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / phosphorylation / 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 / Tyrosine protein kinases specific active-site signature. ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / 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
Similarity search - Domain/homology
Chem-EVR / Fibroblast growth factor receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsEchizen, Y. / Tateishi, Y. / Amano, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.
Authors: Kuriwaki, I. / Kameda, M. / Hisamichi, H. / Kikuchi, S. / Iikubo, K. / Kawamoto, Y. / Moritomo, H. / Kondoh, Y. / Amano, Y. / Tateishi, Y. / Echizen, Y. / Iwai, Y. / Noda, A. / Tomiyama, H. ...Authors: Kuriwaki, I. / Kameda, M. / Hisamichi, H. / Kikuchi, S. / Iikubo, K. / Kawamoto, Y. / Moritomo, H. / Kondoh, Y. / Amano, Y. / Tateishi, Y. / Echizen, Y. / Iwai, Y. / Noda, A. / Tomiyama, H. / Suzuki, T. / Hirano, M.
History
DepositionFeb 4, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Nov 29, 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:
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Assembly

Deposited unit
A: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4102
Polymers35,6651
Non-polymers7451
Water55831
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14590 Å2
Unit cell
Length a, b, c (Å)48.143, 61.225, 59.645
Angle α, β, γ (deg.)90.000, 112.980, 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: 35664.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR3, JTK4 / Production host: Escherichia coli (E. coli)
References: UniProt: P22607, receptor protein-tyrosine kinase
#2: Chemical ChemComp-EVR / 2-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]pyrimidin-4-yl]amino]-N-ethyl-benzenesulfonamide


Mass: 744.946 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H52N8O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.27 Å3/Da / Density % sol: 45.79 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: Citric Acid, PEG 8000

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NE3A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Dec 13, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.53→50 Å / Num. obs: 10740 / % possible obs: 99.4 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.073 / Χ2: 2.206 / Net I/σ(I): 13.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.54-2.5830.375061.271196.4
2.58-2.633.30.3915291.341198.9
2.63-2.683.40.3685441.358199.6
2.68-2.743.60.3415271.3641100
2.74-2.83.70.2895401.4391100
2.8-2.863.70.2355401.3891100
2.86-2.933.70.2295211.4411100
2.93-3.013.70.1635521.5551100
3.01-3.13.70.1535151.6061100
3.1-3.23.70.1145501.7841100
3.2-3.313.70.0955361.8661100
3.31-3.453.70.0825421.9491100
3.45-3.63.70.075362.262199.8
3.6-3.793.70.0685432.634199.8
3.79-4.033.70.0635462.8921100
4.03-4.343.70.065423.2661100
4.34-4.783.60.0575493.35199.6
4.78-5.473.60.0575403.344199.6
5.47-6.893.60.0575463.2861100
6.89-503.20.0555364.606194

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0253refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3B2T

3b2t


Resolution: 2.53→29.36 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.896 / SU B: 12.568 / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.996 / ESU R Free: 0.347 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2789 520 4.8 %RANDOM
Rwork0.2074 ---
obs0.2109 10205 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 131.43 Å2 / Biso mean: 56.476 Å2 / Biso min: 26.48 Å2
Baniso -1Baniso -2Baniso -3
1--2.43 Å2-0 Å2-1.7 Å2
2--2.34 Å2-0 Å2
3---1.13 Å2
Refinement stepCycle: final / Resolution: 2.53→29.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2296 0 53 31 2380
Biso mean--51 57.07 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122405
X-RAY DIFFRACTIONr_angle_refined_deg1.6031.6993258
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7265286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.68622.193114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.31515416
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2151516
X-RAY DIFFRACTIONr_chiral_restr0.1150.2293
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021908
LS refinement shellResolution: 2.53→2.59 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.301 35 -
Rwork0.276 680 -
obs--91.55 %

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