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- PDB-7dhl: Crystal structure of FGFR3 in complex with pyrimidine derivative -

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Basic information

Entry
Database: PDB / ID: 7dhl
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 / 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-H6X / Fibroblast growth factor receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.57 Å
AuthorsEchizen, Y. / Tateishi, Y. / Amano, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.
Authors: Kuriwaki, I. / Kameda, M. / Iikubo, K. / Hisamichi, H. / Kawamoto, Y. / Kikuchi, S. / Moritomo, H. / Kondoh, Y. / Terasaka, T. / Amano, Y. / Tateishi, Y. / Echizen, Y. / Iwai, Y. / Noda, A. ...Authors: Kuriwaki, I. / Kameda, M. / Iikubo, K. / Hisamichi, H. / Kawamoto, Y. / Kikuchi, S. / Moritomo, H. / Kondoh, Y. / Terasaka, T. / Amano, Y. / Tateishi, Y. / Echizen, Y. / Iwai, Y. / Noda, A. / Tomiyama, H. / Nakazawa, T. / Hirano, M.
History
DepositionNov 16, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 3, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 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:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2112
Polymers35,6651
Non-polymers5471
Water25214
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 area15130 Å2
Unit cell
Length a, b, c (Å)48.140, 61.400, 59.895
Angle α, β, γ (deg.)90.000, 112.880, 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-H6X / 5-[2-(3,5-dimethoxyphenyl)ethyl]-N-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidin-2-amine


Mass: 546.704 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H42N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.29 Å3/Da / Density % sol: 46.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5
Details: Citric Acid, Ammonium dihydrogen phosphate, PEG 3350

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Dec 10, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.57→44.35 Å / Num. obs: 10336 / % possible obs: 99.6 % / Redundancy: 3.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.035 / Rrim(I) all: 0.068 / Net I/σ(I): 11.8 / Num. measured all: 38332
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.57-2.683.70.454474312760.8820.2720.532.299.4
8.9-44.353.30.0248252480.9990.0160.02928.492.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PSQ

2psq


Resolution: 2.57→44.35 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.898 / SU B: 13.351 / SU ML: 0.273 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.238 / ESU R Free: 0.325 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2535 484 4.7 %RANDOM
Rwork0.1934 ---
obs0.1965 9839 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 129.18 Å2 / Biso mean: 50.892 Å2 / Biso min: 24.62 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å2-0 Å2-0.03 Å2
2---0.08 Å2-0 Å2
3---0.12 Å2
Refinement stepCycle: final / Resolution: 2.57→44.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2307 0 40 14 2361
Biso mean--57.24 40.39 -
Num. residues----289
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122403
X-RAY DIFFRACTIONr_angle_refined_deg1.3751.6693253
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1855287
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.42522.174115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.95815417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8491516
X-RAY DIFFRACTIONr_chiral_restr0.1050.2294
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021848
LS refinement shellResolution: 2.57→2.637 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 29 -
Rwork0.265 732 -
all-761 -
obs--98.83 %

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