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- PDB-6yoj: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 6-[4-(3-Me... -

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Basic information

Entry
Database: PDB / ID: 6yoj
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 6-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-3,4-dihydro-1H-quinolin-2-one
ComponentsFocal adhesion kinase 1
KeywordsTRANSFERASE / PROTEIN TYROSINE KINASE / ATP BINDING / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-P4N / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.361 Å
AuthorsMusil, D. / Heinrich, T.
CitationJournal: Cell Chem Biol / Year: 2021
Title: Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.
Authors: Berger, B.T. / Amaral, M. / Kokh, D.B. / Nunes-Alves, A. / Musil, D. / Heinrich, T. / Schroder, M. / Neil, R. / Wang, J. / Navratilova, I. / Bomke, J. / Elkins, J.M. / Muller, S. / Frech, M. ...Authors: Berger, B.T. / Amaral, M. / Kokh, D.B. / Nunes-Alves, A. / Musil, D. / Heinrich, T. / Schroder, M. / Neil, R. / Wang, J. / Navratilova, I. / Bomke, J. / Elkins, J.M. / Muller, S. / Frech, M. / Wade, R.C. / Knapp, S.
History
DepositionApr 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 10, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 2, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Jan 24, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)32,7962
Polymers32,3041
Non-polymers4911
Water6,557364
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.525, 48.396, 129.325
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 32304.221 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: Trichoplusia ni (cabbage looper)
References: UniProt: Q05397, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-P4N / 6-[[4-[(3-methylsulfonylphenyl)methylamino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3,4-dihydro-1~{H}-quinolin-2-one


Mass: 491.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F3N5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 364 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.06 Å3/Da / Density % sol: 40.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 16% PEG 3350, 0.1 M TRIS, pH 8.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 9, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.361→45.33 Å / Num. obs: 360917 / % possible obs: 89.8 % / Redundancy: 7.6 % / Biso Wilson estimate: 13.89 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.09 / Net I/σ(I): 16
Reflection shellResolution: 1.361→1.442 Å / Num. unique obs: 2385 / CC1/2: 0.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
PHASERphasing
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.25data extraction
STARANISOdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GU6

4gu6


Resolution: 1.361→45.33 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.948 / SU R Cruickshank DPI: 0.065 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.072 / SU Rfree Blow DPI: 0.072 / SU Rfree Cruickshank DPI: 0.067
RfactorNum. reflection% reflectionSelection details
Rfree0.1984 2435 5.1 %RANDOM
Rwork0.1706 ---
obs0.1719 47762 89.8 %-
Displacement parametersBiso max: 58.51 Å2 / Biso mean: 16.96 Å2 / Biso min: 5.77 Å2
Baniso -1Baniso -2Baniso -3
1-0.7258 Å20 Å20 Å2
2--0.0112 Å20 Å2
3----0.737 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: final / Resolution: 1.361→45.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2081 0 34 365 2480
Biso mean--10.03 28.54 -
Num. residues----259
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d835SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes401HARMONIC5
X-RAY DIFFRACTIONt_it2316HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion291SEMIHARMONIC5
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_contact2690SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2316HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3164HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.99
X-RAY DIFFRACTIONt_other_torsion13.69
LS refinement shellResolution: 1.361→1.41 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3079 46 4.81 %
Rwork0.2492 910 -
Refinement TLS params.Method: refined / Origin x: -6.8878 Å / Origin y: -1.0604 Å / Origin z: 16.4463 Å
111213212223313233
T-0.0125 Å20.0008 Å2-0.0003 Å2--0.0117 Å2-0.0006 Å2---0.0234 Å2
L0.1958 °20.1957 °2-0.2082 °2-0.6903 °2-0.4746 °2--0.6013 °2
S0.0068 Å °-0.0096 Å °-0.0118 Å °0.0228 Å °-0.0468 Å °-0.0162 Å °0.0148 Å °0.0426 Å °0.04 Å °
Refinement TLS groupSelection details: { A|* }

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