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- PDB-6yxv: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N... -

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Basic information

Entry
Database: PDB / ID: 6yxv
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-{3-[(2-phenylamino-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyridin-2-yl}-methanesulfonamide
ComponentsFocal adhesion kinase 1PTK2
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 / regulation of cytoskeleton organization / 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 / Fc-gamma receptor signaling pathway involved in phagocytosis / p130Cas linkage to MAPK signaling for integrins / positive regulation of epithelial cell migration / negative regulation of cell-cell adhesion / 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 / positive regulation of epithelial to mesenchymal transition / ephrin receptor signaling pathway / positive regulation of protein kinase activity / vascular endothelial growth factor receptor signaling pathway / regulation of cell adhesion / 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 / placenta development / protein tyrosine phosphatase activity / molecular function activator activity / cell motility / integrin-mediated signaling pathway / axon guidance / FCGR3A-mediated phagocytosis / 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 / angiogenesis / protein tyrosine kinase activity / dendritic spine / Extra-nuclear estrogen signaling / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cytoskeleton / positive regulation of cell migration / positive regulation of protein phosphorylation / focal adhesion / intracellular membrane-bounded organelle / 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 / 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-Q2H / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.298 Å
AuthorsMusil, D. / Heinrich, T. / Amaral, M.
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
DepositionMay 4, 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

Downloads & links

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Assembly

Deposited unit
A: Focal adhesion kinase 1
B: Focal adhesion kinase 1
C: Focal adhesion kinase 1
D: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,1159
Polymers129,2174
Non-polymers1,8985
Water2,486138
1
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7552
Polymers32,3041
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8513
Polymers32,3041
Non-polymers5472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7552
Polymers32,3041
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7552
Polymers32,3041
Non-polymers4501
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)118.050, 77.127, 174.934
Angle α, β, γ (deg.)90.000, 101.340, 90.000
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: 32304.221 Da / Num. of mol.: 4
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-Q2H / ~{N}-methyl-~{N}-[3-[(~{E})-[2-phenylazanyl-5-(trifluoromethyl)pyrimidin-4-yl]iminomethyl]pyridin-2-yl]methanesulfonamide


Mass: 450.437 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H17F3N6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.02 Å3/Da / Density % sol: 59.29 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / Details: 15% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99998 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 2.298→171.52 Å / Num. obs: 44522 / % possible obs: 92.6 % / Redundancy: 3.3 % / CC1/2: 0.999 / Rpim(I) all: 0.035 / Rrim(I) all: 0.064 / Net I/σ(I): 12.3
Reflection shellResolution: 2.298→2.568 Å / Num. unique obs: 2226 / CC1/2: 0.71 / Rpim(I) all: 0.427 / Rrim(I) all: 0.792

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Processing

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

4gu6


Resolution: 2.298→171.52 Å / Cor.coef. Fo:Fc: 0.91 / Cor.coef. Fo:Fc free: 0.881 / SU R Cruickshank DPI: 0.499 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.465 / SU Rfree Blow DPI: 0.263 / SU Rfree Cruickshank DPI: 0.271
RfactorNum. reflection% reflectionSelection details
Rfree0.232 2217 4.98 %RANDOM
Rwork0.202 ---
obs0.2035 44522 92.6 %-
Displacement parametersBiso max: 124.4 Å2 / Biso mean: 60.78 Å2 / Biso min: 24.75 Å2
Baniso -1Baniso -2Baniso -3
1-3.8023 Å20 Å24.935 Å2
2--2.9037 Å20 Å2
3----6.706 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.298→171.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8387 0 129 138 8654
Biso mean--48.29 41.3 -
Num. residues----1043
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3074SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1529HARMONIC5
X-RAY DIFFRACTIONt_it8714HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1102SEMIHARMONIC5
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_contact6185SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8714HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg11797HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion17.56
LS refinement shellResolution: 2.3→2.47 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2681 34 3.82 %
Rwork0.2269 857 -
all0.2284 891 -
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)
10.3648-0.3693-0.96332.8752-2.17685.04650.1190.13-0.01320.0737-0.18650.1379-0.1034-0.16880.0675-0.0593-0.0558-0.00590.0131-0.027-0.207220.228914.12278.1887
20.98890.4292-1.43421.5389-1.07644.2885-0.2189-0.0886-0.2321-0.0882-0.0177-0.19580.0995-0.0520.2365-0.0623-0.15640.0716-0.063-0.0311-0.071318.309-13.724443.1158
32.73220.1842-1.6281.29040.18073.1845-0.21130.0109-0.22820.00940.1538-0.04110.12450.19690.0575-0.0894-0.2090.04310.0254-0.0286-0.16442.60699.621752.4555
42.2266-0.6401-2.92881.54141.99926.0971-0.21520.1101-0.00750.2049-0.1540.32370.23430.02090.36920.0832-0.0140.187-0.21-0.0024-0.165814.4732.289978.9201
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A414 - 686
2X-RAY DIFFRACTION2{ B|* }B415 - 686
3X-RAY DIFFRACTION3{ C|* }C414 - 686
4X-RAY DIFFRACTION4{ D|* }D415 - 686

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