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- PDB-6gcw: Focal Adhesion Kinase catalytic domain in complex with irreversib... -

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Basic information

Entry
Database: PDB / ID: 6gcw
TitleFocal Adhesion Kinase catalytic domain in complex with irreversible inhibitor
ComponentsFocal adhesion kinase 1PTK2
KeywordsCELL ADHESION / Focal Adhesion Kinase Cell Adhesion Signalling Irreversible inhibitor 2 / 4-pyrimidine derivatives
Function / homology
Function and homology information


Apoptotic cleavage of cellular proteins / NCAM signaling for neurite out-growth / RHO GTPases Activate WASPs and WAVEs / RAF/MAP kinase cascade / Regulation of actin dynamics for phagocytic cup formation / radial glia-guided pyramidal neuron migration / negative regulation of protein autophosphorylation / calcium-dependent cysteine-type endopeptidase activity / positive regulation of substrate-dependent cell migration, cell attachment to substrate / Integrin signaling ...Apoptotic cleavage of cellular proteins / NCAM signaling for neurite out-growth / RHO GTPases Activate WASPs and WAVEs / RAF/MAP kinase cascade / Regulation of actin dynamics for phagocytic cup formation / radial glia-guided pyramidal neuron migration / negative regulation of protein autophosphorylation / calcium-dependent cysteine-type endopeptidase activity / positive regulation of substrate-dependent cell migration, cell attachment to substrate / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / angiogenesis involved in wound healing / signal complex assembly / response to pH / negative regulation of cell-substrate adhesion / wound healing, spreading of cells / positive regulation of focal adhesion assembly / negative regulation of anoikis / positive regulation of protein tyrosine kinase activity / regulation of cell adhesion / response to muscle stretch / ciliary basal body / molecular function activator activity / actin filament organization / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / sarcolemma / integrin binding / positive regulation of protein binding / cell cortex / protein tyrosine kinase activity / angiogenesis / protease binding / dendritic spine / protein autophosphorylation / positive regulation of cell migration / focal adhesion / centrosome / positive regulation of cell population proliferation / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / 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-EUQ / Focal adhesion kinase 1
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsYen-Pon, E. / Li, B. / Acebron-Garcia-de-Eulate, M. / Tomkiewicz-Raulet, C. / Dawson, J. / Lietha, D. / Frame, M.C. / Coumoul, X. / Garbay, C. / Etheve-Quelquejeu, M. / Chen, H.
CitationJournal: Acs Chem.Biol. / Year: 2018
Title: Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase.
Authors: Yen-Pon, E. / Li, B. / Acebron-Garcia-de-Eulate, M. / Tomkiewicz-Raulet, C. / Dawson, J. / Lietha, D. / Frame, M.C. / Coumoul, X. / Garbay, C. / Etheve-Quelquejeu, M. / Chen, H.
History
DepositionApr 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / reflns / reflns_shell
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _reflns.pdbx_Rpim_I_all / _reflns.pdbx_Rrim_I_all / _reflns_shell.Rmerge_I_obs / _reflns_shell.pdbx_CC_half / _reflns_shell.pdbx_Rpim_I_all / _reflns_shell.pdbx_Rrim_I_all
Revision 1.2May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
B: Focal adhesion kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6865
Polymers63,4642
Non-polymers1,2223
Water5,405300
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1640 Å2
ΔGint-7 kcal/mol
Surface area24380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.916, 119.798, 52.810
Angle α, β, γ (deg.)90.00, 90.56, 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 / p41/p43FRNK / Protein-tyrosine kinase 2 / ...FADK 1 / Focal adhesion kinase-related nonkinase / p41/p43FRNK / Protein-tyrosine kinase 2 / p125FAK / pp125FAK


Mass: 31731.805 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: PTK2, FAK, FAK1 / Production host: unidentified baculovirus
References: UniProt: Q00944, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-EUQ / 2-[[5-chloranyl-2-[[4-[[[1-[2-(propanoylamino)ethyl]-1,2,3-triazol-4-yl]methylamino]methyl]phenyl]amino]pyrimidin-4-yl]amino]-~{N}-methyl-benzamide


Mass: 563.054 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H31ClN10O2
#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.: 300 / 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: 2.24 Å3/Da / Density % sol: 45.06 %
Crystal growTemperature: 291.1 K / Method: evaporation / pH: 8.5
Details: TRDYEIQRERIELGRCIGEGQFGDVHQGIYMSPENPALAVAIKTCKNCTSDSVREKFLQEALTMRQFDHPHIVKLIGVI TENPVWIIMELCTLGELRSFLQVRKYSLDLASLILYAYQLSTALAYLESKRFVHRDIAARNVLVSSNDCVKLGDFGLSRY ...Details: TRDYEIQRERIELGRCIGEGQFGDVHQGIYMSPENPALAVAIKTCKNCTSDSVREKFLQEALTMRQFDHPHIVKLIGVI TENPVWIIMELCTLGELRSFLQVRKYSLDLASLILYAYQLSTALAYLESKRFVHRDIAARNVLVSSNDCVKLGDFGLSRY MEDSTYYKASKGKLPIKWMAPESINFRRFTSASDVWMFGVCMWEILMHGVKPFQGVKNNDVIGRIENGERLPMPPNCPPT LYSLMTKCWAYDPSRRPRFTELKAQLSTILEEEKLQ

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Data collection

DiffractionMean temperature: 124 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Nov 22, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2→44.91 Å / Num. obs: 36844 / % possible obs: 97.74 % / Redundancy: 1.5 % / CC1/2: 0.951 / Rmerge(I) obs: 0.121 / Rpim(I) all: 0.117 / Rrim(I) all: 0.168 / Net I/σ(I): 6.8
Reflection shellResolution: 2→2.072 Å / Rmerge(I) obs: 0.742 / Num. unique obs: 3709 / CC1/2: 0.384 / Rpim(I) all: 0.699 / Rrim(I) all: 1.022 / % possible all: 98.85

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
Aimlessdata scaling
RefinementResolution: 2→44.91 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.11
RfactorNum. reflection% reflection
Rfree0.2743 1812 4.92 %
Rwork0.2169 --
obs0.2197 36824 97.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2→44.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4124 0 85 300 4509
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094319
X-RAY DIFFRACTIONf_angle_d1.0515842
X-RAY DIFFRACTIONf_dihedral_angle_d5.4833143
X-RAY DIFFRACTIONf_chiral_restr0.054634
X-RAY DIFFRACTIONf_plane_restr0.006741
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0001-2.05420.36611560.29592720X-RAY DIFFRACTION99
2.0542-2.11460.32321400.28342712X-RAY DIFFRACTION99
2.1146-2.18290.30651250.27062712X-RAY DIFFRACTION99
2.1829-2.26090.40361160.33332683X-RAY DIFFRACTION97
2.2609-2.35140.30051540.25762688X-RAY DIFFRACTION99
2.3514-2.45840.29611380.24512729X-RAY DIFFRACTION99
2.4584-2.5880.28831300.24182737X-RAY DIFFRACTION99
2.588-2.75020.30231460.23452716X-RAY DIFFRACTION99
2.7502-2.96250.27671520.23622693X-RAY DIFFRACTION98
2.9625-3.26060.34071470.2152672X-RAY DIFFRACTION97
3.2606-3.73220.24891300.18752712X-RAY DIFFRACTION97
3.7322-4.70160.221180.16712667X-RAY DIFFRACTION97
4.7016-48.33520.21111600.17662571X-RAY DIFFRACTION92

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