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- PDB-6lvl: Crystal structure of FGFR2 in complex with 1,3,5-triazine derivative -

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Basic information

Entry
Database: PDB / ID: 6lvl
TitleCrystal structure of FGFR2 in complex with 1,3,5-triazine derivative
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / protein kinase / SIGNALING PROTEIN
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 / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus 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 / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / lacrimal gland development / otic vesicle formation / prostate gland morphogenesis / bud elongation involved in lung branching / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / epithelial cell proliferation involved in salivary gland morphogenesis / orbitofrontal cortex development / branching involved in labyrinthine layer morphogenesis / morphogenesis of embryonic epithelium / mesenchymal cell proliferation involved in lung development / epidermis morphogenesis / branching morphogenesis of a nerve / lung-associated mesenchyme development / gland morphogenesis / embryonic organ morphogenesis / branching involved in salivary gland morphogenesis / limb bud formation / endochondral bone growth / reproductive structure development / embryonic digestive tract morphogenesis / membranous septum morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / lung lobe morphogenesis / organ growth / branching involved in prostate gland morphogenesis / mesenchymal cell differentiation / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / positive regulation of phospholipase activity / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / positive regulation of mesenchymal cell proliferation / Phospholipase C-mediated cascade; FGFR2 / embryonic cranial skeleton morphogenesis / regulation of osteoblast proliferation / fibroblast growth factor receptor activity / embryonic pattern specification / lung alveolus development / pyramidal neuron development / outflow tract septum morphogenesis / ureteric bud development / hair follicle morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / digestive tract development / inner ear morphogenesis / bone morphogenesis / odontogenesis / skeletal system morphogenesis / midbrain development / Signaling by FGFR2 IIIa TM / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / fibroblast growth factor receptor signaling pathway / ventricular cardiac muscle tissue morphogenesis / bone mineralization / positive regulation of cell division / cell fate commitment / fibroblast growth factor binding / negative regulation of keratinocyte proliferation / epithelial to mesenchymal transition / lung development / embryonic organ development / PI3K Cascade / post-embryonic development / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / positive regulation of cardiac muscle cell proliferation / positive regulation of Wnt signaling pathway / cellular response to retinoic acid / positive regulation of vascular associated smooth muscle cell proliferation / SHC-mediated cascade:FGFR2 / axonogenesis / FRS-mediated FGFR2 signaling / epithelial cell differentiation / Signaling by FGFR2 in disease / positive regulation of cell cycle / peptidyl-tyrosine phosphorylation / animal organ morphogenesis / positive regulation of epithelial cell proliferation / excitatory synapse / Negative regulation of FGFR2 signaling / bone development / receptor protein-tyrosine kinase / in utero embryonic development / Constitutive Signaling by Aberrant PI3K in Cancer
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EVL / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.98 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:
MolmilJmol/JSmol

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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)73,1608
Polymers71,6122
Non-polymers1,5486
Water00
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4843
Polymers35,8061
Non-polymers6782
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-15 kcal/mol
Surface area14500 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6765
Polymers35,8061
Non-polymers8704
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-16 kcal/mol
Surface area14250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.675, 116.136, 64.202
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 35806.238 Da / Num. of mol.: 2
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-EVL / N-ethyl-2-[[4-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulfonamide


Mass: 581.733 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H39N9O3S / Feature type: SUBJECT OF INVESTIGATION
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: 2.75 Å3/Da / Density % sol: 55.28 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: Tris, Ammonium sulfate, 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 24, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.98→50 Å / Num. obs: 14661 / % possible obs: 87.7 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.119 / Χ2: 2.161 / Net I/σ(I): 9.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.99-3.043.90.3577581.645191.3
3.04-3.13.80.3077541.661192
3.1-3.163.90.2687301.645191
3.16-3.2240.2417551.614190.4
3.22-3.293.90.1917211.767191.2
3.29-3.3740.1867481.871190.8
3.37-3.453.90.1617422.174189.4
3.45-3.543.90.1557452.239189.4
3.54-3.653.90.1317132.219188.9
3.65-3.773.80.1337652.755189.7
3.77-3.93.90.1067072.261188
3.9-4.063.90.1087292.67187.5
4.06-4.243.90.1017402.571188.3
4.24-4.473.90.0877272.719188.3
4.47-4.753.80.097142.757185.8
4.75-5.1140.0867312.326186.3
5.11-5.6340.097322.127185.9
5.63-6.444.10.0877252.094185
6.44-8.114.10.077201.94182.5
8.11-503.90.0517052.277175.5

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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: 2.98→28.11 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.854 / SU B: 15.993 / SU ML: 0.293 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.461 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2506 721 4.9 %RANDOM
Rwork0.2019 ---
obs0.2043 13920 87.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 85.9 Å2 / Biso mean: 26.484 Å2 / Biso min: 8.68 Å2
Baniso -1Baniso -2Baniso -3
1--1.18 Å2-0 Å2-0 Å2
2---0.03 Å20 Å2
3---1.21 Å2
Refinement stepCycle: final / Resolution: 2.98→28.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4576 0 102 0 4678
Biso mean--35.3 --
Num. residues----574
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0124778
X-RAY DIFFRACTIONr_angle_refined_deg1.6581.6746464
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3585570
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.48522.552239
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.02515859
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4911530
X-RAY DIFFRACTIONr_chiral_restr0.1270.2595
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023686
LS refinement shellResolution: 2.982→3.059 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 51 -
Rwork0.294 1016 -
all-1067 -
obs--87.46 %

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