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

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Basic information

Entry
Database: PDB / ID: 6lvk
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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / 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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / otic vesicle formation / prostate gland morphogenesis / regulation of smooth muscle cell differentiation / orbitofrontal cortex development / regulation of morphogenesis of a branching structure / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / branching morphogenesis of a nerve / embryonic organ morphogenesis / endochondral bone growth / morphogenesis of embryonic epithelium / epidermis morphogenesis / bud elongation involved in lung branching / positive regulation of epithelial cell proliferation involved in lung morphogenesis / pyramidal neuron development / membranous septum morphogenesis / reproductive structure development / limb bud formation / 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 prostate gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in labyrinthine layer 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 / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / embryonic pattern specification / outflow tract septum morphogenesis / positive regulation of phospholipase activity / lung-associated mesenchyme development / mesodermal cell differentiation / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / digestive tract development / bone morphogenesis / skeletal system morphogenesis / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / Signaling by FGFR2 IIIa TM / inner ear morphogenesis / organ growth / midbrain development / hair follicle morphogenesis / lung alveolus development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / fibroblast growth factor binding / PI-3K cascade:FGFR2 / bone mineralization / prostate epithelial cord elongation / positive regulation of cell division / excitatory synapse / positive regulation of Wnt signaling pathway / PI3K Cascade / negative regulation of keratinocyte proliferation / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / cell fate commitment / embryonic organ development / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / regulation of ERK1 and ERK2 cascade / post-embryonic development / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation
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. / Immunoglobulin subtype ...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-EVC / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsEchizen, Y. / Amano, Y. / Tateishi, 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)73,3528
Polymers71,7722
Non-polymers1,5806
Water2,198122
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5803
Polymers35,8861
Non-polymers6942
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-14 kcal/mol
Surface area14390 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7725
Polymers35,8861
Non-polymers8864
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint-29 kcal/mol
Surface area14250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.272, 105.571, 116.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 35886.215 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-EVC / N-ethyl-2-[[4-[[4-(4-methylpiperazin-1-yl)-3-(2-morpholin-4-ylethoxy)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzenesulfonamide


Mass: 597.732 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H39N9O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.75 Å3/Da / Density % sol: 55.24 %
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: 95 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: Aug 30, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.29→48.06 Å / Num. obs: 36222 / % possible obs: 99.7 % / Redundancy: 3.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.047 / Rrim(I) all: 0.091 / Net I/σ(I): 9.7
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
2.29-2.373.60.4421251334850.8220.2690.5192.399.7
8.87-48.063.10.02520086490.9980.0170.0324.392

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0253refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3B2T

3b2t


Resolution: 2.29→48.06 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.917 / SU B: 6.897 / SU ML: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.267 / ESU R Free: 0.215 / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.247 1775 4.9 %RANDOM
Rwork0.2035 ---
obs0.2056 34404 99.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 110.08 Å2 / Biso mean: 32.682 Å2 / Biso min: 11.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.51 Å2-0 Å20 Å2
2---0.47 Å20 Å2
3----0.04 Å2
Refinement stepCycle: final / Resolution: 2.29→48.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4584 0 104 122 4810
Biso mean--34.38 29.47 -
Num. residues----574
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0124790
X-RAY DIFFRACTIONr_angle_refined_deg1.7351.6836480
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7555570
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.50822.574237
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.65315857
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0791530
X-RAY DIFFRACTIONr_chiral_restr0.1220.2596
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023714
LS refinement shellResolution: 2.29→2.349 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 133 -
Rwork0.257 2453 -
all-2586 -
obs--99.42 %

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