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- PDB-6yq1: FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N... -

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Basic information

Entry
Database: PDB / ID: 6yq1
TitleFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH N-Methyl-N-(3-{[2-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide
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 fibroblast migration / positive regulation of macrophage proliferation ...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 fibroblast migration / positive regulation of macrophage proliferation / DCC mediated attractive signaling / regulation of osteoblast differentiation / growth hormone receptor signaling pathway / Signal regulatory protein family interactions / MET activates PTK2 signaling / Fc-gamma receptor signaling pathway involved in phagocytosis / regulation of focal adhesion assembly / regulation of GTPase activity / positive regulation of wound healing / establishment of cell polarity / p130Cas linkage to MAPK signaling for integrins / negative regulation of cell-cell adhesion / positive regulation of macrophage chemotaxis / positive regulation of epithelial cell migration / Apoptotic cleavage of cellular proteins / regulation of cytoskeleton organization / regulation of cell adhesion mediated by integrin / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of anoikis / ephrin receptor signaling pathway / positive regulation of protein kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / regulation of cell adhesion / vascular endothelial growth factor receptor signaling pathway / heart morphogenesis / positive regulation of epithelial to mesenchymal transition / stress fiber / EPHB-mediated forward signaling / Integrin signaling / NCAM signaling for neurite out-growth / SH2 domain binding / transforming growth factor beta receptor signaling pathway / ciliary basal body / protein tyrosine phosphatase activity / axon guidance / molecular function activator activity / integrin-mediated signaling pathway / cell motility / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / non-membrane spanning protein tyrosine kinase activity / regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / placenta development / Regulation of actin dynamics for phagocytic cup formation / VEGFA-VEGFR2 Pathway / peptidyl-tyrosine phosphorylation / integrin binding / cell migration / regulation of cell shape / regulation of cell population proliferation / actin binding / cell cortex / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / angiogenesis / protein autophosphorylation / Extra-nuclear estrogen signaling / dendritic spine / 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. / 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 / 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-P7N / Focal adhesion kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.784 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
DepositionApr 16, 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)131,42210
Polymers129,2174
Non-polymers2,2056
Water16,610922
1
A: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9454
Polymers32,3041
Non-polymers6413
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8262
Polymers32,3041
Non-polymers5221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8262
Polymers32,3041
Non-polymers5221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8262
Polymers32,3041
Non-polymers5221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)112.532, 75.749, 173.265
Angle α, β, γ (deg.)90.000, 102.370, 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-P7N / ~{N}-methyl-~{N}-[3-[[[2-[(2-oxidanylidene-3,4-dihydro-1~{H}-quinolin-6-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide


Mass: 521.515 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H22F3N7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 922 / 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: 2.79 Å3/Da / Density % sol: 55.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 15% PEG 3350, 0.2 M Na acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X13 / Wavelength: 1.033226 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033226 Å / Relative weight: 1
ReflectionResolution: 1.784→169.25 Å / Num. obs: 82421 / % possible obs: 93.2 % / Redundancy: 4.1 % / CC1/2: 0.998 / Rrim(I) all: 0.087 / Net I/σ(I): 10.5
Reflection shellResolution: 1.784→2.021 Å / Num. unique obs: 4121 / CC1/2: 0.786 / Rrim(I) all: 0.686

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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: 1.784→169.25 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.924 / SU R Cruickshank DPI: 0.181 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.191 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.2139 4085 4.96 %RANDOM
Rwork0.183 ---
obs0.1845 82421 60.9 %-
Displacement parametersBiso max: 84.9 Å2 / Biso mean: 30.99 Å2 / Biso min: 10.93 Å2
Baniso -1Baniso -2Baniso -3
1-0.1078 Å20 Å21.2806 Å2
2--2.9467 Å20 Å2
3----3.0544 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 1.784→169.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8576 0 150 922 9648
Biso mean--21.78 37.4 -
Num. residues----1065
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3193SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1504HARMONIC5
X-RAY DIFFRACTIONt_it9027HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1139SEMIHARMONIC5
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_contact7778SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9027HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg12244HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion3.26
X-RAY DIFFRACTIONt_other_torsion15.3
LS refinement shellResolution: 1.784→1.91 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2562 84 5.09 %
Rwork0.2151 1565 -
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)
10.8850.1925-1.01360.6572-0.05291.9459-0.0451-0.0218-0.0971-0.07450.0275-0.0476-0.0745-0.03560.0176-0.0266-0.05730.0235-0.0216-0.0266-0.081818.0075-9.954942.9547
21.1068-0.3559-0.14830.2204-0.08961.03910.06630.043-0.125-0.04840.01010.0423-0.07840.0574-0.0765-0.0244-0.03360.0074-0.027-0.0263-0.045839.66913.167452.4406
30.35470.1448-0.66560.4671-0.53312.0618-0.02190.056-0.00450.01270.009-0.05210.0417-0.10920.0128-0.0367-0.03810.01840.0052-0.0257-0.06627.2909-0.818792.0654
40.16490.0376-0.32662.0451-0.70862.77140.02560.02950.09210.0228-0.05210.16080.1517-0.08830.0265-0.0674-0.00060.0167-0.01770.0179-0.106318.453117.53957.8482
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A415 - 686
2X-RAY DIFFRACTION2{ B|* }B410 - 686
3X-RAY DIFFRACTION3{ C|* }C412 - 686
4X-RAY DIFFRACTION4{ D|* }D415 - 686

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