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- PDB-7ozy: FGFR2 kinase domain (residues 461-763) in complex with 38. -

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Basic information

Entry
Database: PDB / ID: 7ozy
TitleFGFR2 kinase domain (residues 461-763) in complex with 38.
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE / FGFR2 / Inhibitor / receptor tyrosine 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 / inner ear morphogenesis / hair follicle 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 / FRS-mediated FGFR2 signaling / positive regulation of cell cycle / 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
Chem-47I / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsTrinh, C.H. / Turner, L.D. / Fishwick, C.W.G.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/K501402/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor.
Authors: Turner, L.D. / Trinh, C.H. / Hubball, R.A. / Orritt, K.M. / Lin, C.C. / Burns, J.E. / Knowles, M.A. / Fishwick, C.W.G.
History
DepositionJun 29, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Fibroblast growth factor receptor 2
BBB: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,6067
Polymers69,6082
Non-polymers9975
Water1,36976
1
AAA: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2723
Polymers34,8041
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
BBB: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3344
Polymers34,8041
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)113.839, 113.839, 117.408
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 34804.215 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 BL21(DE3) (bacteria)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical ChemComp-47I / 4-[3-(4-piperazin-4-ium-1-ylphenyl)-1H-indazol-6-yl]phenol / 4-[3-(4-piperazin-1-ylphenyl)-1H-indazol-6-yl]phenol (uncharged compound's name)


Mass: 371.455 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / 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: 2.73 Å3/Da / Density % sol: 54.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 25% w/v PEG 3350, 0.1 M ammonium sulfate, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Nov 29, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.28→80.54 Å / Num. obs: 35802 / % possible obs: 99.9 % / Redundancy: 7.1 % / CC1/2: 0.989 / Rmerge(I) obs: 0.141 / Rpim(I) all: 0.056 / Rrim(I) all: 0.152 / Net I/σ(I): 6.6
Reflection shellResolution: 2.28→2.34 Å / Rmerge(I) obs: 2.588 / Num. unique obs: 2594 / CC1/2: 0.683 / Rpim(I) all: 1.389 / Rrim(I) all: 2.777

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Processing

Software
NameVersionClassification
DIALSdata reduction
Aimless0.5.32data scaling
PHASER2.7.17phasing
REFMAC5.8.0258refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PVF

2pvf


Resolution: 2.28→80.5 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.894 / SU B: 9.172 / SU ML: 0.216 / Cross valid method: FREE R-VALUE / ESU R: 0.304 / ESU R Free: 0.254
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2959 1691 4.802 %
Rwork0.2403 33525 -
all0.243 --
obs-35216 98.3 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 50.923 Å2
Baniso -1Baniso -2Baniso -3
1--1.096 Å20 Å20 Å2
2---1.096 Å20 Å2
3---2.192 Å2
Refinement stepCycle: LAST / Resolution: 2.28→80.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4389 0 70 76 4535
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134564
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174255
X-RAY DIFFRACTIONr_angle_refined_deg1.431.6666185
X-RAY DIFFRACTIONr_angle_other_deg1.1861.5939854
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1885556
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.05422.422223
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.41615788
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3831528
X-RAY DIFFRACTIONr_chiral_restr0.0630.2578
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025024
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02934
X-RAY DIFFRACTIONr_nbd_refined0.1880.2868
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1770.23947
X-RAY DIFFRACTIONr_nbtor_refined0.1590.22179
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0760.21911
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2112
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other00.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2670.211
X-RAY DIFFRACTIONr_nbd_other0.1940.255
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1640.24
X-RAY DIFFRACTIONr_mcbond_it3.6755.3992236
X-RAY DIFFRACTIONr_mcbond_other3.6715.3972235
X-RAY DIFFRACTIONr_mcangle_it5.5658.0822788
X-RAY DIFFRACTIONr_mcangle_other5.5648.0842789
X-RAY DIFFRACTIONr_scbond_it3.6865.6272328
X-RAY DIFFRACTIONr_scbond_other3.6865.6272329
X-RAY DIFFRACTIONr_scangle_it5.7158.3073397
X-RAY DIFFRACTIONr_scangle_other5.7148.3073398
X-RAY DIFFRACTIONr_lrange_it8.08858.8315238
X-RAY DIFFRACTIONr_lrange_other8.08958.8255231
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.279-2.3380.3561200.35324160.35325800.7230.72998.29460.353
2.338-2.4020.3641180.3423750.34125380.7240.78198.2270.334
2.402-2.4720.3891100.31623250.31924710.7690.81398.54310.308
2.472-2.5480.3461410.30722150.3124010.8170.82798.12580.298
2.548-2.6310.3581140.30121590.30423270.8250.8597.67940.288
2.631-2.7240.353950.27721330.2822700.8610.8798.14980.256
2.724-2.8260.311930.27620410.27721720.8660.8998.25050.258
2.826-2.9410.351920.26619540.2720890.8690.89397.94160.25
2.941-3.0720.293730.26119320.26220420.8760.89898.1880.246
3.072-3.2220.276970.25318080.25419440.8980.90697.99380.241
3.222-3.3960.31040.25116860.25518300.8860.997.81420.246
3.396-3.6010.316810.23916580.24217580.8850.91398.91920.241
3.601-3.8490.256770.23615590.23816580.9350.92898.67310.248
3.849-4.1570.26650.22414470.22515370.9160.92798.37350.245
4.157-4.5530.231790.18613510.18814500.9380.94998.62070.211
4.553-5.0880.251670.1712130.17413040.9470.96198.15950.199
5.088-5.8710.231560.19310940.19511650.950.96198.71240.223
5.871-7.1810.339540.2239310.2299950.8770.9398.9950.252
7.181-10.1160.335330.197670.1968020.9020.94399.75060.227
10.116-80.4970.353220.3214610.3234910.8770.85498.37070.523

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