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- PDB-4ra5: Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a ... -

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Basic information

Entry
Database: PDB / ID: 4ra5
TitleHuman Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)
ComponentsHUMAN PROTEIN KINASE C THETA
KeywordsTransferase/transferase inhibitor / PKC THETA KINASE / kinase domain / PROTEROS BIOSTRUCTURES GMBH / 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 / positive regulation of interleukin-4 production / 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 telomerase activity / positive regulation of telomere maintenance via telomerase / positive regulation of interleukin-2 production / negative regulation of insulin receptor signaling pathway / cell chemotaxis / regulation of cell growth / axon guidance / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / FCERI mediated NF-kB activation / G alpha (z) signalling events / 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-3L0 / Protein kinase C theta type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.61 Å
AuthorsArgiriadi, M.A. / George, D.M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Optimized Protein Kinase C theta (PKC theta ) Inhibitors Reveal Only Modest Anti-inflammatory Efficacy in a Rodent Model of Arthritis.
Authors: George, D.M. / Breinlinger, E.C. / Argiriadi, M.A. / Zhang, Y. / Wang, J. / Bansal-Pakala, P. / Duignan, D.B. / Honore, P. / Lang, Q. / Mittelstadt, S. / Rundell, L. / Schwartz, A. / Sun, J. / Edmunds, J.J.
History
DepositionSep 9, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 4, 2015Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)80,1517
Polymers79,1932
Non-polymers9585
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-14 kcal/mol
Surface area31210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.822, 77.026, 147.547
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-3L0 / (1R)-9-[(1,3-dimethylazetidin-3-yl)(methyl)amino]-1-methyl-8-phenyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one / (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)


Mass: 405.493 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H27N5O2
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 2.83 Å3/Da / Density % sol: 56.55 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 4.25
Details: PEG 3350, MgCl2, sodium acetate and sodium malonate, pH 4.25, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00001 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
11.000011
211
ReflectionResolution: 2.61→73.77 Å / Num. obs: 26584 / % possible obs: 99.1 % / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.047
Reflection shellResolution: 2.61→2.86 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.444 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementResolution: 2.61→73.77 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / SU B: 28.3 / SU ML: 0.281 / Cross valid method: THROUGHOUT / ESU R: 0.664 / ESU R Free: 0.334 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27681 912 3.5 %RANDOM
Rwork0.22817 ---
obs0.22982 25436 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 71.678 Å2
Baniso -1Baniso -2Baniso -3
1-8.66 Å20 Å20 Å2
2---4.38 Å20 Å2
3----4.28 Å2
Refinement stepCycle: LAST / Resolution: 2.61→73.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5375 0 69 24 5468
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0215395
X-RAY DIFFRACTIONr_bond_other_d0.0020.024728
X-RAY DIFFRACTIONr_angle_refined_deg1.1231.9627321
X-RAY DIFFRACTIONr_angle_other_deg0.914310907
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0045652
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.01124.198262
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.40615.07858
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4321522
X-RAY DIFFRACTIONr_chiral_restr0.0680.2761
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026063
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021178
X-RAY DIFFRACTIONr_nbd_refined0.1580.2986
X-RAY DIFFRACTIONr_nbd_other0.1290.24457
X-RAY DIFFRACTIONr_nbtor_refined0.1610.22610
X-RAY DIFFRACTIONr_nbtor_other0.0730.22726
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2109
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.040.22
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0410.24
X-RAY DIFFRACTIONr_symmetry_vdw_other0.0940.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0820.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.82223248
X-RAY DIFFRACTIONr_mcbond_other0.15721314
X-RAY DIFFRACTIONr_mcangle_it1.47635186
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.22842226
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.37562131
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: 2.612→2.68 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.469 74 -
Rwork0.349 1853 -
obs--99.18 %
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)
12.40440.5170.77832.2882-0.81154.74630.03790.0463-0.21190.01890.1089-0.57920.14070.6565-0.1469-0.07710.0871-0.0398-0.0615-0.0895-0.025-19.106-4.777-26.829
21.7371-0.2393-0.14752.23370.46992.65240.04330.0624-0.0018-0.0106-0.0172-0.11860.04330.0667-0.0261-0.13530.0298-0.008-0.2535-0.0236-0.214-37.795-0.638-31.25
34.6072-0.3033-1.81434.62220.08224.03460.297-0.7385-0.48290.4763-0.28080.45741.0198-0.1338-0.01610.4663-0.3092-0.13210.3362-0.0210.132-29.072-8.268.322
40.96960.85381.0044.42291.66944.11490.2489-0.16520.0960.4308-0.46160.75790.4589-0.65040.2126-0.1237-0.16520.01280.1887-0.10780.0929-29.26314.9387.512
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A374 - 460
2X-RAY DIFFRACTION2A461 - 707
3X-RAY DIFFRACTION3B375 - 460
4X-RAY DIFFRACTION4B461 - 701

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