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- PDB-5f9e: Structure of Protein Kinase C theta with compound 10: 2,2-dimethy... -

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Basic information

Entry
Database: PDB / ID: 5f9e
TitleStructure of Protein Kinase C theta with compound 10: 2,2-dimethyl-7-(2-oxidanylidene-3~{H}-imidazo[4,5-b]pyridin-1-yl)-1-(phenylmethyl)-3~{H}-quinazolin-4-one
ComponentsProtein kinase C theta type
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / 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-5VS / Protein kinase C theta type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsKlein, M.
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKC theta inhibitors.
Authors: Katoh, T. / Takai, T. / Yukawa, T. / Tsukamoto, T. / Watanabe, E. / Mototani, H. / Arita, T. / Hayashi, H. / Nakagawa, H. / Klein, M.G. / Zou, H. / Sang, B.C. / Snell, G. / Nakada, Y.
History
DepositionDec 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2016Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein kinase C theta type
B: Protein kinase C theta type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,7094
Polymers83,9102
Non-polymers7992
Water2,954164
1
A: Protein kinase C theta type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3552
Polymers41,9551
Non-polymers3991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Protein kinase C theta type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3552
Polymers41,9551
Non-polymers3991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.603, 76.786, 149.304
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 kinase C theta type / nPKC-theta


Mass: 41955.156 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCQ, PRKCT / Production host: unidentified baculovirus / References: UniProt: Q04759, protein kinase C
#2: Chemical ChemComp-5VS / 2,2-dimethyl-7-(2-oxidanylidene-3~{H}-imidazo[4,5-b]pyridin-1-yl)-1-(phenylmethyl)-3~{H}-quinazolin-4-one


Mass: 399.445 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.57 Å3/Da / Density % sol: 52.12 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 0.1M Hepes pH 7, 0.2M lithium citrate, and 18% PEG M.W. 3,350, 1% hexanediol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 59517 / % possible obs: 97.4 % / Redundancy: 6.9 % / Net I/σ(I): 29.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→41.8 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.948 / SU B: 7.979 / SU ML: 0.108 / Cross valid method: THROUGHOUT / ESU R: 0.165 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23333 2929 5.1 %RANDOM
Rwork0.19681 ---
obs0.19862 54956 97.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 54.729 Å2
Baniso -1Baniso -2Baniso -3
1-2.74 Å20 Å20 Å2
2---1.84 Å20 Å2
3----0.9 Å2
Refinement stepCycle: LAST / Resolution: 2→41.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5248 0 60 164 5472
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0195499
X-RAY DIFFRACTIONr_bond_other_d0.0010.025180
X-RAY DIFFRACTIONr_angle_refined_deg1.4221.9737417
X-RAY DIFFRACTIONr_angle_other_deg0.784311958
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2645641
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.54924.014279
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.338151007
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3341530
X-RAY DIFFRACTIONr_chiral_restr0.090.2753
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0216122
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021324
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 192 -
Rwork0.299 3328 -
obs--82.17 %
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)
11.30980.4868-0.17541.7655-0.08711.66860.05370.0250.0296-0.1174-0.01780.16790.036-0.1571-0.03580.15160.004-0.00640.01990.01920.093432.67474.92430.2966
21.1108-0.39650.43182.9367-1.03892.93420.05030.0362-0.05880.0633-0.1405-0.4380.41830.36180.09010.23720.1107-0.09960.30610.03560.25729.744684.1102-8.8861
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A374 - 709
2X-RAY DIFFRACTION1A1001
3X-RAY DIFFRACTION2B375 - 700
4X-RAY DIFFRACTION2B1001

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