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- PDB-6yvy: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1... -

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Basic information

Entry
Database: PDB / ID: 6yvy
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide
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 / JUN kinase binding / signal complex assembly / positive regulation of ubiquitin-dependent protein catabolic process / positive regulation of macrophage proliferation / DCC mediated attractive signaling ...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 / JUN kinase binding / signal complex assembly / positive regulation of ubiquitin-dependent protein catabolic process / positive regulation of macrophage proliferation / DCC mediated attractive signaling / positive regulation of fibroblast migration / Signal regulatory protein family interactions / regulation of GTPase activity / growth hormone receptor signaling pathway / MET activates PTK2 signaling / regulation of focal adhesion assembly / negative regulation of cell-cell adhesion / positive regulation of wound healing / p130Cas linkage to MAPK signaling for integrins / regulation of osteoblast differentiation / Apoptotic cleavage of cellular proteins / establishment of cell polarity / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / regulation of cell adhesion mediated by integrin / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / GRB2:SOS provides linkage to MAPK signaling for Integrins / regulation of protein phosphorylation / negative regulation of anoikis / positive regulation of epithelial cell migration / ephrin receptor signaling pathway / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / positive regulation of protein kinase activity / vascular endothelial growth factor receptor signaling pathway / regulation of cell adhesion / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / stress fiber / EPHB-mediated forward signaling / Integrin signaling / protein tyrosine phosphatase activity / NCAM signaling for neurite out-growth / transforming growth factor beta receptor signaling pathway / SH2 domain binding / axon guidance / molecular function activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / cell motility / placenta development / peptidyl-tyrosine phosphorylation / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / integrin binding / cell migration / regulation of cell shape / regulation of cell population proliferation / positive regulation of protein phosphorylation / actin binding / RAF/MAP kinase cascade / cell cortex / protein autophosphorylation / protein tyrosine kinase activity / protein phosphatase binding / angiogenesis / cytoskeleton / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ciliary basal body / cilium / positive regulation of cell migration / focal adhesion / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / centrosome / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / ATP binding / nucleus / plasma membrane / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-P1E / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.918 Å
AuthorsMusil, D. / 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
DepositionApr 28, 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
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)131,1479
Polymers129,2174
Non-polymers1,9305
Water9,116506
1
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7632
Polymers32,3041
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7632
Polymers32,3041
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8593
Polymers32,3041
Non-polymers5552
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7632
Polymers32,3041
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)113.974, 75.856, 172.640
Angle α, β, γ (deg.)90.000, 102.660, 90.000
Int Tables number5
Space group name H-MC121

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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.: 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-P1E / 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide


Mass: 458.501 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H25F3N6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 506 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.82 Å3/Da / Density % sol: 56.34 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 7.5 / 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: 0.99977 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99977 Å / Relative weight: 1
ReflectionResolution: 1.918→56.49 Å / Num. obs: 88953 / % possible obs: 85.6 % / Redundancy: 4.9 % / CC1/2: 0.997 / Rpim(I) all: 0.035 / Rrim(I) all: 0.08 / Net I/σ(I): 11.9
Reflection shellResolution: 1.918→1.978 Å / Redundancy: 5.1 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 4447 / CC1/2: 0.73 / Rpim(I) all: 0.366 / Rrim(I) all: 0.872

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Processing

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

4gu6


Resolution: 1.918→56.49 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.915 / SU R Cruickshank DPI: 0.181 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.182 / SU Rfree Blow DPI: 0.153 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.2353 4419 4.97 %RANDOM
Rwork0.2141 ---
obs0.2151 88941 85.6 %-
Displacement parametersBiso max: 122.94 Å2 / Biso mean: 39.24 Å2 / Biso min: 7.98 Å2
Baniso -1Baniso -2Baniso -3
1-4.0328 Å20 Å21.468 Å2
2---0.9833 Å20 Å2
3----3.0495 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.918→56.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8323 0 129 507 8959
Biso mean--34.93 36.44 -
Num. residues----1035
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3110SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1505HARMONIC5
X-RAY DIFFRACTIONt_it8584HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1115SEMIHARMONIC5
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_contact7498SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8720HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg11822HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion15.18
LS refinement shellResolution: 1.92→1.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2551 85 4.78 %
Rwork0.2429 1694 -
all0.2435 1779 -
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)
10.22270.1848-0.22350.5659-0.44291.15750.01880.00330.01010.02890.0078-0.018-0.0376-0.0742-0.02650.00740.00380.019-0.1098-0.002-0.066827.0820.18997.6185
20.8734-0.4537-0.48050.78930.27161.8053-0.021-0.0484-0.14570.16330.02570.07070.004-0.063-0.00470.00240.05160.0269-0.09650.0391-0.106119.928630.490440.927
31.1374-0.0039-0.24510.4642-0.11111.25670.005-0.0498-0.07550.02320.0310.0101-0.0443-0.0429-0.0359-0.01690.03290.0036-0.12160.0018-0.094654.883916.5432.4119
41.014-0.354-0.78642.85312.82915.95730.052-0.13270.09970.28920.0687-0.183-0.19310.4165-0.12070.12680.01960.0058-0.17440.0008-0.331875.788618.680776.6964
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A412 - 686
2X-RAY DIFFRACTION2{ B|* }B415 - 686
3X-RAY DIFFRACTION3{ C|* }C411 - 686
4X-RAY DIFFRACTION4{ D|* }D415 - 686

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