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- PDB-4h1j: Crystal structure of PYK2 with the pyrazole 13a -

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Basic information

Entry
Database: PDB / ID: 4h1j
TitleCrystal structure of PYK2 with the pyrazole 13a
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 / 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 / peptidyl-tyrosine autophosphorylation / 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 / vascular endothelial growth factor receptor signaling pathway / bone resorption / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / cellular defense response / regulation of cell adhesion / cellular response to retinoic acid / ionotropic glutamate receptor binding / positive regulation of endothelial cell migration / ionotropic glutamate receptor signaling pathway / peptidyl-tyrosine phosphorylation / tumor necrosis factor-mediated signaling pathway / 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 / positive regulation of neuron projection development / regulation of synaptic plasticity / VEGFA-VEGFR2 Pathway / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / neuron migration / positive regulation of angiogenesis / presynapse / lamellipodium / regulation of cell shape / growth cone / cell body / protein autophosphorylation / protein-containing complex assembly / protein tyrosine kinase activity / cell cortex / adaptive immune response / negative regulation of neuron apoptotic process / cytoskeleton / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / positive regulation of cell migration / negative regulation of cell population proliferation / focal adhesion / neuronal cell body / positive regulation of cell population proliferation / apoptotic process / 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-0YH / Protein-tyrosine kinase 2-beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsHan, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors.
Authors: Bhattacharya, S.K. / Aspnes, G.E. / Bagley, S.W. / Boehm, M. / Brosius, A.D. / Buckbinder, L. / Chang, J.S. / Dibrino, J. / Eng, H. / Frederick, K.S. / Griffith, D.A. / Griffor, M.C. / ...Authors: Bhattacharya, S.K. / Aspnes, G.E. / Bagley, S.W. / Boehm, M. / Brosius, A.D. / Buckbinder, L. / Chang, J.S. / Dibrino, J. / Eng, H. / Frederick, K.S. / Griffith, D.A. / Griffor, M.C. / Guimaraes, C.R. / Guzman-Perez, A. / Han, S. / Kalgutkar, A.S. / Klug-McLeod, J. / Garcia-Irizarry, C. / Li, J. / Lippa, B. / Price, D.A. / Southers, J.A. / Walker, D.P. / Wei, L. / Xiao, J. / Zawistoski, M.P. / Zhao, X.
History
DepositionSep 10, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: Protein-tyrosine kinase 2-beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4512
Polymers33,9921
Non-polymers4591
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.945, 82.923, 85.728
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Protein-tyrosine kinase 2-beta / PYK2 / Calcium-dependent tyrosine kinase / CADTK / Calcium-regulated non-receptor proline-rich ...PYK2 / Calcium-dependent tyrosine kinase / CADTK / Calcium-regulated non-receptor proline-rich tyrosine kinase / Cell adhesion kinase beta / CAK-beta / CAKB / Focal adhesion kinase 2 / FADK 2 / Proline-rich tyrosine kinase 2 / Related adhesion focal tyrosine kinase / RAFTK


Mass: 33992.320 Da / Num. of mol.: 1 / Fragment: protein kinase domain (UNP residues 416-692)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTK2B, FAK2, PYK2, RAFTK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q14289, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-0YH / 1-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-[3-(4-methoxy-2-methylphenyl)-1H-pyrazol-5-yl]urea


Mass: 458.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / 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: 1.98 Å3/Da / Density % sol: 38 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Bis-Tris, 0.2 M magnesium chloride, 20-27% PEG3350, 1 mM TCEP, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 1, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 19032 / Num. obs: 18708 / % possible obs: 98.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 20.27 Å2
Reflection shellResolution: 2→2.07 Å / % possible all: 93.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
BUSTER2.11.2refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→19.97 Å / Cor.coef. Fo:Fc: 0.9356 / Cor.coef. Fo:Fc free: 0.9122 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.188 / SU Rfree Blow DPI: 0.15 / SU Rfree Cruickshank DPI: 0.147 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2094 967 5.18 %RANDOM
Rwork0.1803 ---
obs0.1818 18674 98.68 %-
Displacement parametersBiso mean: 23.99 Å2
Baniso -1Baniso -2Baniso -3
1-2.395 Å20 Å20 Å2
2--2.2082 Å20 Å2
3----4.6033 Å2
Refine analyzeLuzzati coordinate error obs: 0.219 Å
Refinement stepCycle: LAST / Resolution: 2→19.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2130 0 34 137 2301
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092215HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023000HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d768SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes311HARMONIC5
X-RAY DIFFRACTIONt_it2215HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion18.04
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
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_contact2581SEMIHARMONIC4
LS refinement shellResolution: 2→2.12 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2246 151 5.37 %
Rwork0.1774 2663 -
all0.18 2814 -
obs--98.68 %
Refinement TLS params.Method: refined / Origin x: 1.4631 Å / Origin y: 1.6264 Å / Origin z: 7.308 Å
111213212223313233
T-0.0036 Å20.0104 Å20.0021 Å2--0.001 Å20.0064 Å2--0.0051 Å2
L0.6219 °20.3517 °2-0.0716 °2-0.6726 °2-0.2227 °2--0.3367 °2
S-0.0217 Å °-0.0224 Å °-0.0581 Å °0.0053 Å °0.0148 Å °-0.0071 Å °0.0469 Å °-0.0072 Å °0.0069 Å °
Refinement TLS groupSelection details: { A|* }

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