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- PDB-5to8: Selectivity switch between FAK and Pyk2: Macrocyclization of FAK ... -

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Basic information

Entry
Database: PDB / ID: 5to8
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 / neurotransmitter receptor regulator activity / response to cation stress / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / 3-phosphoinositide-dependent protein kinase binding / regulation of ubiquitin-dependent protein catabolic process / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation / regulation of postsynaptic density assembly ...regulation of macrophage chemotaxis / neurotransmitter receptor regulator activity / response to cation stress / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / 3-phosphoinositide-dependent protein kinase binding / regulation of ubiquitin-dependent protein catabolic process / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation / regulation of postsynaptic density assembly / blood vessel endothelial cell migration / negative regulation of muscle cell apoptotic process / negative regulation of bone mineralization / cortical cytoskeleton organization / apical dendrite / positive regulation of ubiquitin-dependent protein catabolic process / activation of Janus kinase activity / regulation of release of sequestered calcium ion into cytosol / cellular response to fluid shear stress / focal adhesion assembly / signal complex assembly / chemokine-mediated signaling pathway / NMDA selective glutamate receptor complex / Interleukin-2 signaling / sprouting angiogenesis / long-term synaptic depression / oocyte maturation / Signal regulatory protein family interactions / positive regulation of cell-matrix adhesion / calmodulin-dependent protein kinase activity / positive regulation of DNA biosynthetic process / postsynaptic modulation of chemical synaptic transmission / positive regulation of actin filament polymerization / stress fiber assembly / negative regulation of potassium ion transport / positive regulation of excitatory postsynaptic potential / RHOU GTPase cycle / response to immobilization stress / positive regulation of protein kinase activity / postsynaptic density, intracellular component / glial cell proliferation / glutamate receptor binding / cellular defense response / regulation of cell adhesion / vascular endothelial growth factor receptor signaling pathway / response to glucose / response to mechanical stimulus / cellular response to retinoic acid / peptidyl-tyrosine autophosphorylation / bone resorption / response to cAMP / tumor necrosis factor-mediated signaling pathway / ionotropic glutamate receptor signaling pathway / positive regulation of endothelial cell migration / positive regulation of synaptic transmission, glutamatergic / response to hormone / response to cocaine / positive regulation of translation / response to ischemia / integrin-mediated signaling pathway / long-term synaptic potentiation / regulation of actin cytoskeleton organization / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Schaffer collateral - CA1 synapse / regulation of synaptic plasticity / response to hydrogen peroxide / epidermal growth factor receptor signaling pathway / VEGFA-VEGFR2 Pathway / positive regulation of neuron projection development / response to calcium ion / peptidyl-tyrosine phosphorylation / positive regulation of angiogenesis / : / positive regulation of reactive oxygen species metabolic process / neuron projection development / MAPK cascade / positive regulation of nitric oxide biosynthetic process / presynapse / lamellipodium / cell cortex / regulation of cell shape / positive regulation of cytosolic calcium ion concentration / cell body / growth cone / positive regulation of cell growth / protein-containing complex assembly / protein tyrosine kinase activity / response to ethanol / adaptive immune response / negative regulation of neuron apoptotic process / protein autophosphorylation / dendritic spine / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / cytoskeleton / response to hypoxia
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. / 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-7FM / Protein-tyrosine kinase 2-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.9849 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 1.0Dec 21, 2016Provider: 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)33,1412
Polymers32,5801
Non-polymers5621
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.625, 93.565, 43.214
Angle α, β, γ (deg.)90.00, 93.85, 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-7FM / 25-(methylsulfonyl)-8-(trifluoromethyl)-5,17,18,21,22,23,24,25-octahydro-12H-7,11-(azeno)-16,13-(metheno)pyrido[3,2-i]pyrrolo[1,2-q][1,3,7,11,17]pentaazacyclohenicosin-20(6H)-one


Mass: 561.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26F3N7O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.33 Å3/Da / Density % sol: 47.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 19% PEG1000, 100 mM LiSulfate, 50 mM Disodium hydrogen phosphate, 50 mM Citric Acid

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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: Jun 12, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9849→43.117 Å / Num. obs: 20507 / % possible obs: 99.7 % / Redundancy: 3.3 % / Net I/σ(I): 22.3

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementResolution: 1.9849→43.117 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 23.3
RfactorNum. reflection% reflection
Rfree0.235 2012 9.85 %
Rwork0.2032 --
obs0.2064 20419 99.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9849→43.117 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1927 0 39 83 2049
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072013
X-RAY DIFFRACTIONf_angle_d1.0332741
X-RAY DIFFRACTIONf_dihedral_angle_d15.454729
X-RAY DIFFRACTIONf_chiral_restr0.07308
X-RAY DIFFRACTIONf_plane_restr0.005339
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9849-2.03460.25111280.20891149X-RAY DIFFRACTION90
2.0346-2.08960.25421500.21051335X-RAY DIFFRACTION100
2.0896-2.1510.25481350.20281321X-RAY DIFFRACTION100
2.151-2.22050.24861520.20371332X-RAY DIFFRACTION100
2.2205-2.29980.24731500.21391313X-RAY DIFFRACTION100
2.2998-2.39190.26041540.20551300X-RAY DIFFRACTION100
2.3919-2.50080.23781360.20071361X-RAY DIFFRACTION100
2.5008-2.63260.25251440.20811311X-RAY DIFFRACTION100
2.6326-2.79750.24311500.20971329X-RAY DIFFRACTION100
2.7975-3.01340.26711400.22461323X-RAY DIFFRACTION100
3.0134-3.31660.23021480.21271329X-RAY DIFFRACTION100
3.3166-3.79630.25981380.20121325X-RAY DIFFRACTION100
3.7963-4.78190.20061520.17761339X-RAY DIFFRACTION100
4.7819-43.12690.20891350.20771340X-RAY DIFFRACTION98

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