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- PDB-4ebv: Structure of Focal Adhesion Kinase catalytic domain in complex wi... -

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Basic information

Entry
Database: PDB / ID: 4ebv
TitleStructure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor
ComponentsFocal adhesion kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase Domain / Allosteric inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration ...netrin-activated signaling pathway / regulation of substrate adhesion-dependent cell spreading / regulation of endothelial cell migration / regulation of epithelial cell migration / detection of muscle stretch / positive regulation of ubiquitin-dependent protein catabolic process / JUN kinase binding / signal complex assembly / positive regulation of macrophage proliferation / positive regulation of fibroblast migration / DCC mediated attractive signaling / Signal regulatory protein family interactions / growth hormone receptor signaling pathway / regulation of osteoblast differentiation / MET activates PTK2 signaling / regulation of focal adhesion assembly / establishment of cell polarity / positive regulation of wound healing / negative regulation of cell-cell adhesion / regulation of GTPase activity / positive regulation of macrophage chemotaxis / Fc-gamma receptor signaling pathway involved in phagocytosis / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / regulation of cytoskeleton organization / Apoptotic cleavage of cellular proteins / regulation of cell adhesion mediated by integrin / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of anoikis / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / ephrin receptor signaling pathway / positive regulation of protein kinase activity / regulation of cell adhesion / vascular endothelial growth factor receptor signaling pathway / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / stress fiber / EPHB-mediated forward signaling / NCAM signaling for neurite out-growth / Integrin signaling / SH2 domain binding / transforming growth factor beta receptor signaling pathway / ciliary basal body / protein tyrosine phosphatase activity / molecular function activator activity / integrin-mediated signaling pathway / cell motility / FCGR3A-mediated phagocytosis / axon guidance / non-specific protein-tyrosine kinase / regulation of protein phosphorylation / non-membrane spanning protein tyrosine kinase activity / placenta development / epidermal growth factor receptor signaling pathway / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / cell migration / integrin binding / actin binding / regulation of cell population proliferation / cell cortex / regulation of cell shape / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / angiogenesis / protein autophosphorylation / dendritic spine / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of protein phosphorylation / intracellular membrane-bounded organelle / focal adhesion / centrosome / positive regulation of cell population proliferation / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain ...Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain / FERM/acyl-CoA-binding protein superfamily / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-0O7 / ISOPROPYL ALCOHOL / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.67 Å
AuthorsSkene, R.J. / Hosfield, D.J.
CitationJournal: Eur.J.Med.Chem. / Year: 2013
Title: Discovery and characterization of novel allosteric FAK inhibitors.
Authors: Iwatani, M. / Iwata, H. / Okabe, A. / Skene, R.J. / Tomita, N. / Hayashi, Y. / Aramaki, Y. / Hosfield, D.J. / Hori, A. / Baba, A. / Miki, H.
History
DepositionMar 25, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 22, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Jan 16, 2013Group: Database references
Revision 1.3Mar 27, 2013Group: Database references
Revision 1.4Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5544
Polymers35,0941
Non-polymers4603
Water4,378243
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.222, 47.954, 83.281
Angle α, β, γ (deg.)90.00, 112.45, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-864-

HOH

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Components

#1: Protein Focal adhesion kinase 1 / FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit ...FADK 1 / Focal adhesion kinase-related nonkinase / FRNK / Protein phosphatase 1 regulatory subunit 71 / PPP1R71 / Protein-tyrosine kinase 2 / p125FAK / pp125FAK


Mass: 35094.312 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2, FAK, FAK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0O7 / 8-(4-ethylphenyl)-5-methyl-2,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide


Mass: 339.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N3O2S
#3: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 243 / Source method: isolated from a natural source / Formula: H2O

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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: 1.95 Å3/Da / Density % sol: 36.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG4000, 8% 2-Propanol, 12% Glycerol, 0.1M HEPES, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.99 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 11, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 1.67→50 Å / Num. all: 53368 / Num. obs: 31536 / % possible obs: 89.1 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.042 / Net I/σ(I): 26
Reflection shellResolution: 1.67→1.71 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.193 / Mean I/σ(I) obs: 5 / % possible all: 51.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.2.0005refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MP8

1mp8


Resolution: 1.67→39.31 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.943 / SU B: 4.301 / SU ML: 0.076 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.125 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23563 1415 5 %RANDOM
Rwork0.1874 ---
obs0.18974 26668 88.97 %-
all-53368 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.367 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å2-0.12 Å2
2--0.24 Å20 Å2
3----0.1 Å2
Refinement stepCycle: LAST / Resolution: 1.67→39.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2103 0 32 243 2378
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192204
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1911.9822984
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3335260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.14923.16398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.69315399
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.6861519
X-RAY DIFFRACTIONr_chiral_restr0.0830.2329
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211640
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02431
X-RAY DIFFRACTIONr_nbd_refined0.2160.2413
X-RAY DIFFRACTIONr_nbd_other0.1780.21971
X-RAY DIFFRACTIONr_nbtor_refined0.1790.21046
X-RAY DIFFRACTIONr_nbtor_other0.0790.21155
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1850.2134
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.120.213
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2330.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2420.212
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.75221342
X-RAY DIFFRACTIONr_mcbond_other0.4342513
X-RAY DIFFRACTIONr_mcangle_it2.32832071
X-RAY DIFFRACTIONr_scbond_it1.8552945
X-RAY DIFFRACTIONr_scangle_it2.6363816
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.671→1.714 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 59 -
Rwork0.271 1137 -
obs--51.11 %
Refinement TLS params.Method: refined / Origin x: -10.9339 Å / Origin y: 0.9242 Å / Origin z: -18.4967 Å
111213212223313233
T0.0179 Å20.0192 Å2-0.0008 Å2-0.0374 Å20.006 Å2--0.0087 Å2
L0.2479 °20.2945 °2-0.3123 °2-0.8679 °2-0.1838 °2--0.593 °2
S-0.0159 Å °-0.026 Å °-0.0116 Å °-0.0677 Å °-0.0166 Å °0.0122 Å °0.0432 Å °0.0855 Å °0.0326 Å °

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