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

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Basic information

Entry
Database: PDB / ID: 4ebw
TitleStructure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor
ComponentsFocal adhesion kinase 1PTK2
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 / positive regulation of macrophage chemotaxis / regulation of GTPase activity / negative regulation of cell-cell adhesion / 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 / SH2 domain binding / Integrin signaling / transforming growth factor beta receptor signaling pathway / ciliary basal body / protein tyrosine phosphatase activity / molecular function activator activity / integrin-mediated signaling pathway / cell motility / placenta development / FCGR3A-mediated phagocytosis / axon guidance / regulation of protein phosphorylation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / 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 / dendritic spine / protein autophosphorylation / 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 / cytosol / cytoplasm
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-0PF / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsIwatani, M. / Iwata, H. / Okabe, A. / Skene, R.J. / Tomita, N. / Hayashi, Y. / Aramaki, Y. / Hosfield, D.J. / Hori, A. / Baba, A. / Miki, H.
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 1.0Jul 25, 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

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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)35,4622
Polymers35,0941
Non-polymers3671
Water86548
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)81.300, 47.860, 83.667
Angle α, β, γ (deg.)90.00, 118.39, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Focal adhesion kinase 1 / PTK2 / 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 / Fragment: unp residues 411-686
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-0PF / 1-ethyl-8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide


Mass: 367.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N3O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.04 Å3/Da / Density % sol: 39.71 %
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: SSRL / Beamline: BL7-1 / Wavelength: 0.97 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. all: 15207 / Num. obs: 8832 / % possible obs: 91.5 %

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→30 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.878 / SU B: 30.501 / SU ML: 0.296 / Cross valid method: THROUGHOUT / ESU R Free: 0.41 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.27349 373 4.8 %RANDOM
Rwork0.18209 ---
all0.18629 15207 --
obs0.18629 7418 92.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.106 Å2
Baniso -1Baniso -2Baniso -3
1-7.62 Å20 Å21.39 Å2
2---2.74 Å20 Å2
3----3.56 Å2
Refinement stepCycle: LAST / Resolution: 2.65→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2081 0 26 48 2155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222160
X-RAY DIFFRACTIONr_angle_refined_deg1.2991.982924
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2765256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.30823.22996
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.17515388
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4931518
X-RAY DIFFRACTIONr_chiral_restr0.0890.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211612
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6931.51293
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.33322098
X-RAY DIFFRACTIONr_scbond_it2.2383867
X-RAY DIFFRACTIONr_scangle_it3.644.5826
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.65→2.718 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 19 -
Rwork0.228 410 -
obs--70.56 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.78641.84010.88728.5877-0.86226.71840.03020.29020.1002-0.4753-0.0108-0.13080.01530.2202-0.01940.0573-0.0024-0.04740.18890.05840.153214.983212.31782.9056
21.26640.57520.04314.6864-0.02414.63580.02140.02580.18660.16750.13570.3953-0.3265-0.1365-0.15710.0396-0.02270.00670.28180.05320.258311.590113.726210.8643
31.3338-0.7194-1.26785.69551.97774.7955-0.1033-0.0594-0.05090.61110.16730.16980.21370.2286-0.0640.13870.021-0.01540.17650.02150.167113.1654-3.138319.8951
42.89670.0505-2.33544.63712.29535.6292-0.19970.26410.00350.6387-0.12350.51080.3338-0.47870.32310.1978-0.00670.07880.17980.00830.17723.8511.156724.3881
56.2578-1.1609-2.25174.77722.79595.764-0.35360.3133-0.31511.0456-0.24910.89361.1044-0.58330.60270.5287-0.13380.26130.1438-0.0420.23451.9773-11.319127.2665
611.6979-1.676-7.48096.16493.93628.0642-0.7039-1.2104-0.46332.46490.3293-0.18891.05411.18690.37461.17640.1067-0.09990.30280.12180.091614.4086-7.658133.5795
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A411 - 455
2X-RAY DIFFRACTION2A456 - 505
3X-RAY DIFFRACTION3A506 - 555
4X-RAY DIFFRACTION4A556 - 605
5X-RAY DIFFRACTION5A606 - 655
6X-RAY DIFFRACTION6A656 - 686

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