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- PDB-6agx: The cocrystal structure of FGFR2 bound with compound 14 harboring... -

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Basic information

Entry
Database: PDB / ID: 6agx
TitleThe cocrystal structure of FGFR2 bound with compound 14 harboring 5H-pyrrolo[2,3-b]pyrazine scaffold
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE/INHIBITOR / Tyrosine-protein kinase / TRANSFERASE-INHIBITOR complex
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 / digestive tract development / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / bone morphogenesis / skeletal system morphogenesis / odontogenesis / ureteric bud development / positive regulation of mesenchymal cell proliferation / regulation of osteoblast differentiation / ventricular cardiac muscle tissue morphogenesis / inner ear morphogenesis / Signaling by FGFR2 IIIa TM / organ growth / midbrain development / hair follicle morphogenesis / lung alveolus development / fibroblast growth factor binding / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / 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 / epithelial to mesenchymal transition / negative regulation of keratinocyte proliferation / fibroblast growth factor receptor signaling pathway / embryonic organ development / cell fate commitment / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / FRS-mediated FGFR2 signaling / positive regulation of cardiac muscle cell proliferation / 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 / post-embryonic development / regulation of ERK1 and ERK2 cascade / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / 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-9WX / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.95 Å
AuthorsXiong, B.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDA12020317 China
CitationJournal: To be published
Title: The cocrystal structure of FGFR2 bound with compound 14 harboring 5H-pyrrolo[2,3-b]pyrazine scaffold
Authors: Xiong, B.
History
DepositionAug 15, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 21, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
C: Fibroblast growth factor receptor 2
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,1968
Polymers138,1984
Non-polymers1,9984
Water0
1
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,0984
Polymers69,0992
Non-polymers9992
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2670 Å2
ΔGint-16 kcal/mol
Surface area26970 Å2
MethodPISA
2
C: Fibroblast growth factor receptor 2
D: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,0984
Polymers69,0992
Non-polymers9992
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2640 Å2
ΔGint-14 kcal/mol
Surface area27030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.317, 78.270, 99.251
Angle α, β, γ (deg.)90.000, 96.470, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: THR / End label comp-ID: THR / Refine code: 0 / Auth seq-ID: 467 - 764 / Label seq-ID: 1 - 298

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 34549.496 Da / Num. of mol.: 4 / Fragment: UNP residues 467-764 / Mutation: A628T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-9WX / ethyl [4-({3-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-5-yl}sulfonyl)-1H-imidazol-1-yl]acetate


Mass: 499.540 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C23H25N5O6S

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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: 2.51 Å3/Da / Density % sol: 51.04 %
Crystal growTemperature: 298 K / Method: evaporation / pH: 6.5
Details: 0.2M Ammonium sulfate, 0.1M MES pH 6.5, 30%(w/v) PEG 5000 MME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 11, 2015
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. obs: 27621 / % possible obs: 96.1 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.117 / Rpim(I) all: 0.088 / Rrim(I) all: 0.147 / Χ2: 0.709 / Net I/σ(I): 6.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.95-32.50.75313550.440.580.9560.76997.8
3-3.062.50.68614060.4550.530.8720.75897.6
3.06-3.112.50.55314030.4980.4210.6990.76297.8
3.11-3.182.60.41313940.7160.3120.520.7797.8
3.18-3.252.50.41213750.70.3150.5210.8197.7
3.25-3.322.50.3514010.7670.2620.440.78397.9
3.32-3.412.50.2614120.8530.1940.3260.79597.3
3.41-3.52.50.22513510.8730.170.2830.80396.4
3.5-3.62.30.18713870.9030.1460.2390.82296
3.6-3.722.30.14513760.9170.1130.1840.80796.1
3.72-3.852.50.13313990.9180.0990.1670.81396.8
3.85-42.60.10413710.9340.0760.1290.80396.4
4-4.192.60.0914010.9410.0660.1120.83897.3
4.19-4.412.60.07313940.9620.0530.0910.78196.2
4.41-4.682.60.06413520.9630.0470.080.67594.9
4.68-5.042.50.05513650.9790.040.0690.65694.7
5.04-5.552.30.05113700.9690.0390.0640.5294.3
5.55-6.352.60.04413770.9780.0310.0540.41295.3
6.35-82.60.03813760.9850.0280.0470.34193.9
8-502.40.03813560.9830.0290.0480.4589.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0230refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4J95

4j95


Resolution: 2.95→45.22 Å / Cor.coef. Fo:Fc: 0.896 / Cor.coef. Fo:Fc free: 0.855 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.576
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2984 1269 4.9 %RANDOM
Rwork0.2514 ---
obs0.2537 24653 90.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 148.09 Å2 / Biso mean: 58.986 Å2 / Biso min: 27.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å2-0 Å20.01 Å2
2---0.01 Å20 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 2.95→45.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9380 0 140 0 9520
Biso mean--72.73 --
Num. residues----1165
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0149760
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178929
X-RAY DIFFRACTIONr_angle_refined_deg1.1471.70613219
X-RAY DIFFRACTIONr_angle_other_deg1.3351.66320975
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.32551173
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.6722.448482
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.008151778
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.121564
X-RAY DIFFRACTIONr_chiral_restr0.0460.21216
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0210685
X-RAY DIFFRACTIONr_gen_planes_other0.0050.021703
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A88560.1
12B88560.1
21A89230.1
22C89230.1
31A88480.09
32D88480.09
41B88630.08
42C88630.08
51B94930.08
52D94930.08
61C89100.08
62D89100.08
LS refinement shellResolution: 2.95→3.026 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 62 -
Rwork0.307 1330 -
all-1392 -
obs--66.32 %

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