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- PDB-4q9s: Crystal Structure of human Focal Adhesion Kinase (Fak) bound to C... -

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Basic information

Entry
Database: PDB / ID: 4q9s
TitleCrystal Structure of human Focal Adhesion Kinase (Fak) bound to Compound1 (3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE)
ComponentsFocal adhesion kinase 1PTK2
KeywordsTransferase/transferase inhibitor / Kinase catalytic domain / 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-30G / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsArgiriadi, M.A. / George, D.M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of Selective and Orally Bioavailable Protein Kinase C theta (PKC theta ) Inhibitors from a Fragment Hit.
Authors: George, D.M. / Breinlinger, E.C. / Friedman, M. / Zhang, Y. / Wang, J. / Argiriadi, M. / Bansal-Pakala, P. / Barth, M. / Duignan, D.B. / Honore, P. / Lang, Q. / Mittelstadt, S. / Potin, D. / ...Authors: George, D.M. / Breinlinger, E.C. / Friedman, M. / Zhang, Y. / Wang, J. / Argiriadi, M. / Bansal-Pakala, P. / Barth, M. / Duignan, D.B. / Honore, P. / Lang, Q. / Mittelstadt, S. / Potin, D. / Rundell, L. / Edmunds, J.J.
History
DepositionMay 1, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 2, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2014Group: Database references
Revision 1.2Sep 17, 2014Group: Source and taxonomy
Revision 1.3Sep 24, 2014Group: Source and taxonomy
Revision 1.4Jan 21, 2015Group: Database references
Revision 1.5Nov 22, 2017Group: Refinement description / Category: software
Revision 1.6Mar 6, 2024Group: 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 / software / 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 / _software.name / _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

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Assembly

Deposited unit
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3232
Polymers32,1201
Non-polymers2031
Water2,504139
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.840, 47.200, 63.160
Angle α, β, γ (deg.)90.00, 99.32, 90.00
Int Tables number4
Space group name H-MP1211

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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: 32120.139 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-30G / 3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one


Mass: 203.197 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H9N3O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 139 / 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: 2.1 Å3/Da / Density % sol: 41.41 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: Na acetate, PEG MME2000, pH 5.6, VAPOR DIFFUSION, HANGING DROP, temperature 290.0K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 5, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→47.2 Å / Num. obs: 16304 / % possible obs: 90 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 29.29 Å2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
2.065-2.0722.60.4984.8158198.8
9.559-47.22.90.02828.8181198.9

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Processing

Software
NameVersionClassification
JDirectordata collection
PHASERphasing
BUSTER2.9.7refinement
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→18.6 Å / Cor.coef. Fo:Fc: 0.9421 / Cor.coef. Fo:Fc free: 0.9152 / SU R Cruickshank DPI: 0.199 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2163 819 5.08 %RANDOM
Rwork0.1764 ---
all0.2163 16304 --
obs0.1784 16124 98.19 %-
Displacement parametersBiso mean: 31.94 Å2
Baniso -1Baniso -2Baniso -3
1-0.2816 Å20 Å2-5.4091 Å2
2--3.778 Å20 Å2
3----4.0595 Å2
Refine analyzeLuzzati coordinate error obs: 0.219 Å
Refinement stepCycle: LAST / Resolution: 2.07→18.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2024 0 15 139 2178
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012095HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.042841HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d732SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes48HARMONIC2
X-RAY DIFFRACTIONt_gen_planes302HARMONIC5
X-RAY DIFFRACTIONt_it2095HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.08
X-RAY DIFFRACTIONt_other_torsion17.13
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion268SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2457SEMIHARMONIC4
LS refinement shellResolution: 2.07→2.21 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2735 133 4.7 %
Rwork0.1917 2695 -
all0.1956 2828 -
obs--98.19 %

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