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- PDB-8swe: FGFR2 Kinase Domain Bound to Reversible Inhibitor Cmpd 3 -

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Basic information

Entry
Database: PDB / ID: 8swe
TitleFGFR2 Kinase Domain Bound to Reversible Inhibitor Cmpd 3
ComponentsFibroblast growth factor receptor 2
KeywordsONCOPROTEIN / Inhibitor Kinase
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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / 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 / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / mesenchymal cell differentiation / positive regulation of phospholipase activity / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / branching involved in labyrinthine layer morphogenesis / lung lobe morphogenesis / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / fibroblast growth factor receptor activity / branching involved in salivary gland morphogenesis / embryonic pattern specification / pyramidal neuron development / embryonic cranial skeleton morphogenesis / lung-associated mesenchyme development / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / bone morphogenesis / digestive tract development / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / skeletal system morphogenesis / organ growth / hair follicle morphogenesis / inner ear morphogenesis / Signaling by FGFR2 IIIa TM / lung alveolus development / regulation of osteoblast differentiation / ventricular cardiac muscle tissue morphogenesis / PI-3K cascade:FGFR2 / prostate epithelial cord elongation / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / midbrain development / bone mineralization / fibroblast growth factor binding / positive regulation of cell division / PI3K Cascade / epithelial to mesenchymal transition / excitatory synapse / fibroblast growth factor receptor signaling pathway / cell fate commitment / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / embryonic organ development / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / FRS-mediated FGFR2 signaling / cellular response to retinoic acid / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / lung development / peptidyl-tyrosine phosphorylation / animal organ morphogenesis / positive regulation of epithelial cell proliferation / post-embryonic development / Negative regulation of FGFR2 signaling / receptor protein-tyrosine kinase / bone 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
GLUTATHIONE / : / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
AuthorsValverde, R. / Foster, L.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.
Authors: Schonherr, H. / Ayaz, P. / Taylor, A.M. / Casaletto, J.B. / Toure, B.B. / Moustakas, D.T. / Hudson, B.M. / Valverde, R. / Zhao, S. / O'Hearn, P.J. / Foster, L. / Sharon, D.A. / Garfinkle, S. ...Authors: Schonherr, H. / Ayaz, P. / Taylor, A.M. / Casaletto, J.B. / Toure, B.B. / Moustakas, D.T. / Hudson, B.M. / Valverde, R. / Zhao, S. / O'Hearn, P.J. / Foster, L. / Sharon, D.A. / Garfinkle, S. / Giordanetto, F. / Lescarbeau, A. / Kurukulasuriya, R. / Gerami-Moayed, N. / Maglic, D. / Bruderek, K. / Naik, G. / Gunaydin, H. / Mader, M.M. / Boezio, A.A. / McLean, T.H. / Chen, R. / Wang, Y. / Shaw, D.E. / Watters, J. / Bergstrom, D.A.
History
DepositionMay 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release

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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)73,7189
Polymers72,2432
Non-polymers1,4757
Water2,756153
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9204
Polymers36,1221
Non-polymers7993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7975
Polymers36,1221
Non-polymers6764
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.460, 117.130, 64.860
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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


Mass: 36121.621 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-GSH / GLUTATHIONE


Mass: 307.323 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N3O6S
#4: Chemical ChemComp-WXQ / N-{4-[4-amino-5-(4-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}prop-2-enamide


Mass: 399.445 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 153 / 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: 2.77 Å3/Da / Density % sol: 55.64 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 27 % PEG 4000, 0.1 M Hepes pH7.5, 0.252 M Ammonium Sulfate, 0.05 M GSH GSSG
PH range: 7-8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11584 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11584 Å / Relative weight: 1
ReflectionResolution: 2.23→78.37 Å / Num. obs: 38979 / % possible obs: 99.94 % / Redundancy: 6.7 % / Biso Wilson estimate: 37.85 Å2 / CC1/2: 0.995 / Net I/σ(I): 5.3
Reflection shellResolution: 2.23→2.34 Å / Mean I/σ(I) obs: 1.25 / Num. unique obs: 7553 / CC1/2: 0.75 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RI1

3ri1


Resolution: 2.24→78.37 Å / SU ML: 0.3321 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.337
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2496 1173 3.01 %
Rwork0.2112 37806 -
obs0.2124 38979 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.73 Å2
Refinement stepCycle: LAST / Resolution: 2.24→78.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4577 0 104 153 4834
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00574790
X-RAY DIFFRACTIONf_angle_d0.71596468
X-RAY DIFFRACTIONf_chiral_restr0.0446698
X-RAY DIFFRACTIONf_plane_restr0.005823
X-RAY DIFFRACTIONf_dihedral_angle_d11.5417658
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.24-2.340.42081330.40174314X-RAY DIFFRACTION91.86
2.34-2.470.34271450.29984687X-RAY DIFFRACTION99.98
2.47-2.620.32761470.26044725X-RAY DIFFRACTION99.98
2.62-2.820.31261470.23334736X-RAY DIFFRACTION99.96
2.82-3.110.27991480.24054746X-RAY DIFFRACTION100
3.11-3.560.22881470.19654761X-RAY DIFFRACTION99.98
3.56-4.480.21551500.16944815X-RAY DIFFRACTION99.9
4.48-78.370.20391560.18215022X-RAY DIFFRACTION99.88

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