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- PDB-5tob: Selectivity switch between FAK and Pyk2: Macrocyclization of FAK ... -

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Basic information

Entry
Database: PDB / ID: 5tob
TitleSelectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency
ComponentsProtein-tyrosine kinase 2-beta
KeywordsTransferase/Transferase Inhibitor / kinase / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


regulation of macrophage chemotaxis / response to cation stress / neurotransmitter receptor regulator activity / 3-phosphoinositide-dependent protein kinase binding / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / regulation of ubiquitin-dependent protein catabolic process / blood vessel endothelial cell migration / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation ...regulation of macrophage chemotaxis / response to cation stress / neurotransmitter receptor regulator activity / 3-phosphoinositide-dependent protein kinase binding / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / regulation of ubiquitin-dependent protein catabolic process / blood vessel endothelial cell migration / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation / negative regulation of muscle cell apoptotic process / negative regulation of bone mineralization / cortical cytoskeleton organization / regulation of postsynaptic density assembly / activation of Janus kinase activity / chemokine-mediated signaling pathway / apical dendrite / focal adhesion assembly / cellular response to fluid shear stress / regulation of release of sequestered calcium ion into cytosol / signal complex assembly / positive regulation of ubiquitin-dependent protein catabolic process / calcium/calmodulin-dependent protein kinase activity / Interleukin-2 signaling / long-term synaptic depression / oocyte maturation / sprouting angiogenesis / Signal regulatory protein family interactions / NMDA selective glutamate receptor complex / positive regulation of cell-matrix adhesion / positive regulation of DNA biosynthetic process / positive regulation of actin filament polymerization / stress fiber assembly / negative regulation of potassium ion transport / RHOU GTPase cycle / response to immobilization stress / positive regulation of excitatory postsynaptic potential / positive regulation of protein kinase activity / postsynaptic density, intracellular component / glutamate receptor binding / vascular endothelial growth factor receptor signaling pathway / bone resorption / postsynaptic modulation of chemical synaptic transmission / glial cell proliferation / cellular defense response / regulation of cell adhesion / response to glucose / peptidyl-tyrosine autophosphorylation / response to mechanical stimulus / response to cAMP / tumor necrosis factor-mediated signaling pathway / cellular response to retinoic acid / response to hormone / positive regulation of endothelial cell migration / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / positive regulation of translation / response to ischemia / integrin-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity / regulation of actin cytoskeleton organization / non-specific protein-tyrosine kinase / positive regulation of JNK cascade / response to cocaine / peptidyl-tyrosine phosphorylation / Schaffer collateral - CA1 synapse / regulation of synaptic plasticity / positive regulation of neuron projection development / response to hydrogen peroxide / VEGFA-VEGFR2 Pathway / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / response to calcium ion / positive regulation of angiogenesis / neuron projection development / positive regulation of reactive oxygen species metabolic process / positive regulation of nitric oxide biosynthetic process / MAPK cascade / lamellipodium / regulation of cell shape / presynapse / cell body / growth cone / positive regulation of cytosolic calcium ion concentration / positive regulation of cell growth / cell cortex / protein-containing complex assembly / protein autophosphorylation / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / adaptive immune response / response to ethanol / cytoskeleton / response to hypoxia / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / postsynaptic density / positive regulation of cell migration / protein phosphorylation
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 central domain / FERM/acyl-CoA-binding protein superfamily ...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 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-YAM / Protein-tyrosine kinase 2-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.117 Å
AuthorsNewby, Z.E.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2016
Title: Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.
Authors: Farand, J. / Mai, N. / Chandrasekhar, J. / Newby, Z.E. / Van Veldhuizen, J. / Loyer-Drew, J. / Venkataramani, C. / Guerrero, J. / Kwok, A. / Li, N. / Zherebina, Y. / Wilbert, S. / Zablocki, ...Authors: Farand, J. / Mai, N. / Chandrasekhar, J. / Newby, Z.E. / Van Veldhuizen, J. / Loyer-Drew, J. / Venkataramani, C. / Guerrero, J. / Kwok, A. / Li, N. / Zherebina, Y. / Wilbert, S. / Zablocki, J. / Phillips, G. / Watkins, W.J. / Mourey, R. / Notte, G.T.
History
DepositionOct 17, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 29, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 6, 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: Protein-tyrosine kinase 2-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0872
Polymers32,5801
Non-polymers5071
Water2,198122
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11810 Å2
Unit cell
Length a, b, c (Å)37.584, 93.808, 42.519
Angle α, β, γ (deg.)90.00, 92.53, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Protein-tyrosine kinase 2-beta / Calcium-dependent tyrosine kinase / CADTK / Calcium-regulated non-receptor proline-rich tyrosine ...Calcium-dependent tyrosine kinase / CADTK / Calcium-regulated non-receptor proline-rich tyrosine kinase / Cell adhesion kinase beta / CAKB / Focal adhesion kinase 2 / FADK 2 / Proline-rich tyrosine kinase 2 / Related adhesion focal tyrosine kinase / RAFTK


Mass: 32579.752 Da / Num. of mol.: 1 / Fragment: UNP Residues 414-692
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2B, FAK2, PYK2, RAFTK / Production host: Escherichia coli (E. coli)
References: UniProt: Q14289, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-YAM / N-methyl-N-{3-[({2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}methanesulfonamide


Mass: 507.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20F3N7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.3 Å3/Da / Density % sol: 46.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 25% PEG3350, 100 mM Bis-Tris pH 5.5, 100 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 28, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.117→38.695 Å / Num. obs: 16617 / % possible obs: 97.7 % / Redundancy: 3 % / Net I/σ(I): 9.85

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementResolution: 2.117→38.695 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2615 1604 9.91 %
Rwork0.2061 --
obs0.2116 16184 96.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.117→38.695 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1910 0 35 122 2067
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011993
X-RAY DIFFRACTIONf_angle_d1.0212710
X-RAY DIFFRACTIONf_dihedral_angle_d14.9071186
X-RAY DIFFRACTIONf_chiral_restr0.057302
X-RAY DIFFRACTIONf_plane_restr0.006333
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1174-2.18580.32331220.22741084X-RAY DIFFRACTION80
2.1858-2.26390.26851460.20431296X-RAY DIFFRACTION96
2.2639-2.35450.28121480.20421347X-RAY DIFFRACTION97
2.3545-2.46170.27751440.19621318X-RAY DIFFRACTION98
2.4617-2.59140.30041480.20641352X-RAY DIFFRACTION98
2.5914-2.75370.28741500.21241362X-RAY DIFFRACTION99
2.7537-2.96630.27061440.22361360X-RAY DIFFRACTION99
2.9663-3.26470.26141520.21111369X-RAY DIFFRACTION99
3.2647-3.73670.25181560.20451347X-RAY DIFFRACTION99
3.7367-4.70660.21961470.17841361X-RAY DIFFRACTION98
4.7066-38.70190.24951470.2221384X-RAY DIFFRACTION99

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