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- PDB-4q9z: Human Protein Kinase C Theta in Complex with Compound35 ((1R)-9-(... -

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Basic information

Entry
Database: PDB / ID: 4q9z
TitleHuman Protein Kinase C Theta in Complex with Compound35 ((1R)-9-(AZETIDIN-3-YLAMINO)-1,8-DIMETHYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE)
ComponentsHUMAN PROTEIN KINASE C THETA
KeywordsTransferase/transferase inhibitor / PKC THETA KINASE / kinase catalytic domain / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


positive regulation of T-helper 2 cell activation / protein kinase C / Netrin-1 signaling / diacylglycerol-dependent serine/threonine kinase activity / Effects of PIP2 hydrolysis / regulation of platelet aggregation / CD4-positive, alpha-beta T cell proliferation / positive regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of T cell apoptotic process / positive regulation of T-helper 17 type immune response ...positive regulation of T-helper 2 cell activation / protein kinase C / Netrin-1 signaling / diacylglycerol-dependent serine/threonine kinase activity / Effects of PIP2 hydrolysis / regulation of platelet aggregation / CD4-positive, alpha-beta T cell proliferation / positive regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of T cell apoptotic process / positive regulation of T-helper 17 type immune response / aggresome / Apoptotic cleavage of cellular proteins / positive regulation of interleukin-17 production / Fc-epsilon receptor signaling pathway / positive regulation of telomere capping / membrane protein ectodomain proteolysis / centriolar satellite / immunological synapse / positive regulation of interleukin-4 production / negative regulation of insulin receptor signaling pathway / positive regulation of telomerase activity / positive regulation of telomere maintenance via telomerase / positive regulation of interleukin-2 production / cell chemotaxis / axon guidance / regulation of cell growth / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / G alpha (z) signalling events / FCERI mediated NF-kB activation / RAS processing / Inactivation, recovery and regulation of the phototransduction cascade / positive regulation of T cell activation / Downstream TCR signaling / positive regulation of NF-kappaB transcription factor activity / protein kinase activity / intracellular signal transduction / inflammatory response / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / regulation of DNA-templated transcription / ATP binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Protein kinase C, theta / Novel protein kinase C theta, catalytic domain / Protein kinase C delta/epsilon/eta/theta, C2 domain / Protein kinase C, delta/epsilon/eta/theta types / Protein kinase, C-terminal / Protein kinase C terminal domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. ...Protein kinase C, theta / Novel protein kinase C theta, catalytic domain / Protein kinase C delta/epsilon/eta/theta, C2 domain / Protein kinase C, delta/epsilon/eta/theta types / Protein kinase, C-terminal / Protein kinase C terminal domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C2 domain / C2 domain profile. / C1-like domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / C2 domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / 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-PZW / Protein kinase C theta type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsArgiriadi, M.A. / George, D.M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of Selective and Orally Bioavailable Protein Kinase C theta (PKC theta ) Inhibitors from a Fragment Hit.
Authors: George, D.M. / Breinlinger, E.C. / Friedman, M. / Zhang, Y. / Wang, J. / Argiriadi, M. / Bansal-Pakala, P. / Barth, M. / Duignan, D.B. / Honore, P. / Lang, Q. / Mittelstadt, S. / Potin, D. / ...Authors: George, D.M. / Breinlinger, E.C. / Friedman, M. / Zhang, Y. / Wang, J. / Argiriadi, M. / Bansal-Pakala, P. / Barth, M. / Duignan, D.B. / Honore, P. / Lang, Q. / Mittelstadt, S. / Potin, D. / Rundell, L. / Edmunds, J.J.
History
DepositionMay 2, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 2, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2014Group: Database references
Revision 1.2Sep 17, 2014Group: Source and taxonomy
Revision 1.3Jan 21, 2015Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HUMAN PROTEIN KINASE C THETA
B: HUMAN PROTEIN KINASE C THETA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,8195
Polymers79,1932
Non-polymers6263
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-16 kcal/mol
Surface area30930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.954, 78.575, 146.966
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 HUMAN PROTEIN KINASE C THETA / nPKC-theta


Mass: 39596.516 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN / Mutation: E381I, E538T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCQ, PRKCT / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q04759, protein kinase C
#2: Chemical ChemComp-PZW / (1R)-9-(azetidin-3-ylamino)-1,8-dimethyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one


Mass: 301.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H19N5O2
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.97 Å3/Da / Density % sol: 58.54 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→73.48 Å / Num. obs: 28125 / % possible obs: 96.2 % / Observed criterion σ(I): 0 / Redundancy: 4 % / Rmerge(I) obs: 0.045
Reflection shellResolution: 2.6→2.81 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.45 / % possible all: 98

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 2.6→73.48 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.907 / SU B: 24.825 / SU ML: 0.24 / Cross valid method: THROUGHOUT / ESU R: 0.572 / ESU R Free: 0.304 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25595 921 3.4 %RANDOM
Rwork0.21861 ---
obs0.21987 26124 96.16 %-
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: 65.44 Å2
Baniso -1Baniso -2Baniso -3
1--2.15 Å20 Å20 Å2
2--3.71 Å20 Å2
3----1.56 Å2
Refinement stepCycle: LAST / Resolution: 2.6→73.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5344 0 45 56 5445
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225272
X-RAY DIFFRACTIONr_bond_other_d0.0080.023708
X-RAY DIFFRACTIONr_angle_refined_deg1.0771.9367141
X-RAY DIFFRACTIONr_angle_other_deg0.9942.9828845
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4445641
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.58223.992248
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.77315.053855
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1241523
X-RAY DIFFRACTIONr_chiral_restr0.0660.2756
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215901
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021147
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8223204
X-RAY DIFFRACTIONr_mcbond_other0.13921293
X-RAY DIFFRACTIONr_mcangle_it1.60135121
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.45942068
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.97862016
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.404 79 -
Rwork0.357 1921 -
obs--97.94 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.831.05491.40143.2733-1.9066.4474-0.07020.06430.66090.15740.02130.2733-0.8064-0.21820.04890.19140.13240.02950.13110.03930.296114.173-0.895-10.56
22.3602-0.3861-0.04761.8220.23682.6108-0.04630.09760.12250.02640.08-0.0375-0.11730.0076-0.03370.01730.02140.01860.1257-0.00770.084618.59-20.588-5.864
33.1414-0.77791.17062.93243.09166.1489-0.0752-0.0028-0.5905-0.6519-0.12290.5605-0.2975-1.00780.19810.545-0.195-0.00420.5370.18280.488810.495-11.756-46.384
43.98380.8076-1.17562.0034-0.6093.239-0.2327-0.1219-0.4798-0.00690.0963-0.01940.3922-0.12350.13630.3332-0.09960.04940.17880.11150.287834.407-10.967-45.586
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A375 - 460
2X-RAY DIFFRACTION2A461 - 707
3X-RAY DIFFRACTION3B374 - 460
4X-RAY DIFFRACTION4B461 - 704

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