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- PDB-3h3c: Crystal structure of PYK2 in complex with Sulfoximine-substituted... -

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Basic information

Entry
Database: PDB / ID: 3h3c
TitleCrystal structure of PYK2 in complex with Sulfoximine-substituted trifluoromethylpyrimidine analog
ComponentsProtein tyrosine kinase 2 beta
KeywordsTRANSFERASE / PYK2 / Kinase / Alternative splicing / ATP-binding / Cell membrane / Cytoplasm / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Tyrosine-protein kinase
Function / homology
Function and homology information


regulation of macrophage chemotaxis / neurotransmitter receptor regulator activity / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / regulation of ubiquitin-dependent protein catabolic process / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation / negative regulation of bone mineralization / cortical cytoskeleton organization / regulation of postsynaptic density assembly ...regulation of macrophage chemotaxis / neurotransmitter receptor regulator activity / positive regulation of B cell chemotaxis / marginal zone B cell differentiation / regulation of ubiquitin-dependent protein catabolic process / endothelin receptor signaling pathway / negative regulation of myeloid cell differentiation / negative regulation of bone mineralization / cortical cytoskeleton organization / regulation of postsynaptic density assembly / activation of Janus kinase activity / chemokine-mediated signaling pathway / apical dendrite / 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 / sprouting angiogenesis / Interleukin-2 signaling / Signal regulatory protein family interactions / NMDA selective glutamate receptor complex / positive regulation of cell-matrix adhesion / positive regulation of actin filament polymerization / Golgi organization / negative regulation of potassium ion transport / positive regulation of protein kinase activity / RHOU GTPase cycle / signaling receptor activator activity / positive regulation of excitatory postsynaptic potential / peptidyl-tyrosine autophosphorylation / vascular endothelial growth factor receptor signaling pathway / bone resorption / postsynaptic density, intracellular component / cellular defense response / regulation of cell adhesion / tumor necrosis factor-mediated signaling pathway / cellular response to retinoic acid / ionotropic glutamate receptor binding / positive regulation of endothelial cell migration / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / non-membrane spanning protein tyrosine kinase activity / positive regulation of JNK cascade / non-specific protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / regulation of synaptic plasticity / positive regulation of neuron projection development / VEGFA-VEGFR2 Pathway / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / neuron migration / positive regulation of angiogenesis / lamellipodium / regulation of cell shape / presynapse / cell body / protein autophosphorylation / growth cone / protein-containing complex assembly / cell cortex / protein tyrosine kinase activity / adaptive immune response / negative regulation of neuron apoptotic process / cytoskeleton / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / protein phosphorylation / positive regulation of cell migration / negative regulation of cell population proliferation / focal adhesion / neuronal cell body / apoptotic process / positive regulation of cell population proliferation / dendrite / negative regulation of apoptotic process / perinuclear region of cytoplasm / glutamatergic synapse / signal transduction / 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 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 / 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 / Protein-tyrosine kinase 2-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsHan, S. / Mistry, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity.
Authors: Walker, D.P. / Zawistoski, M.P. / McGlynn, M.A. / Li, J.C. / Kung, D.W. / Bonnette, P.C. / Baumann, A. / Buckbinder, L. / Houser, J.A. / Boer, J. / Mistry, A. / Han, S. / Xing, L. / Guzman-Perez, A.
History
DepositionApr 16, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 26, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein tyrosine kinase 2 beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1297
Polymers32,1901
Non-polymers9396
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.281, 92.830, 42.843
Angle α, β, γ (deg.)90.00, 92.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Protein tyrosine kinase 2 beta / Focal adhesion kinase 2 / FADK 2 / Proline-rich tyrosine kinase 2 / Cell adhesion kinase beta / CAK ...Focal adhesion kinase 2 / FADK 2 / Proline-rich tyrosine kinase 2 / Cell adhesion kinase beta / CAK beta / Calcium-dependent tyrosine kinase / CADTK / Related adhesion focal tyrosine kinase / RAFTK


Mass: 32190.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2B, FAK2, PYK2, RAFTK / Production host: unidentified baculovirus
References: UniProt: Q14289, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: 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.: 1 / Source method: obtained synthetically / Formula: C19H25F3N6O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 46.54 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.2M MgCl2, 20-27% PEG3350, 1mM TCEP, 0.1M bis-Tris, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.542 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Nov 20, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 19055 / Observed criterion σ(I): 2 / Redundancy: 2.8 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 10.1
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 2.03 / Num. unique all: 1852

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Processing

Software
NameClassification
HKL-2000data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→30 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.911 / SU B: 4.893 / SU ML: 0.135 / Cross valid method: THROUGHOUT / ESU R: 0.225 / ESU R Free: 0.197 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.27324 975 5.1 %RANDOM
Rwork0.22235 ---
obs0.22484 18043 96.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 39.514 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å20 Å2-0.2 Å2
2---0.91 Å20 Å2
3---1.74 Å2
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2134 0 56 29 2219
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222238
X-RAY DIFFRACTIONr_angle_refined_deg1.6291.9913036
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9245261
X-RAY DIFFRACTIONr_chiral_restr0.1260.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021636
X-RAY DIFFRACTIONr_nbd_refined0.2210.2983
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.274
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2240.251
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0470.21
X-RAY DIFFRACTIONr_mcbond_it1.1031.51313
X-RAY DIFFRACTIONr_mcangle_it2.03222138
X-RAY DIFFRACTIONr_scbond_it2.8133925
X-RAY DIFFRACTIONr_scangle_it4.5014.5898
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.355 78
Rwork0.314 1266

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