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- PDB-4ra4: Crystal Structure of Human Protein Kinase C Alpha in Complex with... -

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Basic information

Entry
Database: PDB / ID: 4ra4
TitleCrystal Structure of Human Protein Kinase C Alpha in Complex with Compound 28 ((R)-6-((3S,4S)-1,3-Dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)
ComponentsProtein kinase C
KeywordsTransferase/transferase inhibitor / Kinase domain / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


Disinhibition of SNARE formation / Response to elevated platelet cytosolic Ca2+ / positive regulation of angiotensin-activated signaling pathway / desmosome assembly / positive regulation of dense core granule biogenesis / histone H3T6 kinase activity / calcium,diacylglycerol-dependent serine/threonine kinase activity / HuR (ELAVL1) binds and stabilizes mRNA / Depolymerization of the Nuclear Lamina / Trafficking of GluR2-containing AMPA receptors ...Disinhibition of SNARE formation / Response to elevated platelet cytosolic Ca2+ / positive regulation of angiotensin-activated signaling pathway / desmosome assembly / positive regulation of dense core granule biogenesis / histone H3T6 kinase activity / calcium,diacylglycerol-dependent serine/threonine kinase activity / HuR (ELAVL1) binds and stabilizes mRNA / Depolymerization of the Nuclear Lamina / Trafficking of GluR2-containing AMPA receptors / Acetylcholine regulates insulin secretion / ROBO receptors bind AKAP5 / WNT5A-dependent internalization of FZD4 / protein kinase C / negative regulation of glial cell apoptotic process / diacylglycerol-dependent serine/threonine kinase activity / mitotic nuclear membrane disassembly / regulation of platelet aggregation / positive regulation of macrophage differentiation / positive regulation of lipopolysaccharide-mediated signaling pathway / alphav-beta3 integrin-PKCalpha complex / Calmodulin induced events / Syndecan interactions / Regulation of KIT signaling / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cardiac muscle hypertrophy / positive regulation of cell adhesion / RET signaling / RHO GTPases Activate NADPH Oxidases / positive regulation of blood vessel endothelial cell migration / positive regulation of bone resorption / positive regulation of endothelial cell proliferation / regulation of mRNA stability / EGFR Transactivation by Gastrin / response to interleukin-1 / SHC1 events in ERBB2 signaling / positive regulation of endothelial cell migration / positive regulation of mitotic cell cycle / post-translational protein modification / ciliary basal body / VEGFR2 mediated cell proliferation / mitochondrial membrane / apoptotic signaling pathway / peptidyl-threonine phosphorylation / Signaling by SCF-KIT / G alpha (z) signalling events / positive regulation of angiogenesis / Inactivation, recovery and regulation of the phototransduction cascade / integrin binding / Ca2+ pathway / peptidyl-serine phosphorylation / angiogenesis / positive regulation of ERK1 and ERK2 cascade / cell adhesion / protein kinase activity / intracellular signal transduction / positive regulation of cell migration / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / perinuclear region of cytoplasm / enzyme binding / endoplasmic reticulum / mitochondrion / extracellular exosome / zinc ion binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Classical Protein Kinase C alpha, catalytic domain / Protein kinase C, alpha/beta/gamma 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. / C2 domain / Protein kinase C conserved region 2 (CalB) / Zinc finger phorbol-ester/DAG-type profile. ...Classical Protein Kinase C alpha, catalytic domain / Protein kinase C, alpha/beta/gamma 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. / C2 domain / Protein kinase C conserved region 2 (CalB) / 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-3KZ / Protein kinase C / Protein kinase C alpha type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.63 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
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Mar 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / software / struct_conn / 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 / _software.name / _struct_conn.pdbx_leaving_atom_flag / _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 kinase C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2702
Polymers40,8471
Non-polymers4221
Water72140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)112.412, 44.468, 85.502
Angle α, β, γ (deg.)90.00, 114.72, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Protein kinase C /


Mass: 40847.469 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: L7RSM7, UniProt: P17252*PLUS, protein kinase C
#2: Chemical ChemComp-3KZ / (1R)-9-[(3S,4S)-1,3-dimethylpiperidin-4-yl]-8-(2-fluorophenyl)-1-methyl-3,5-dihydro[1,2,4]triazino[3,4-c][1,4]benzoxazin-2(1H)-one


Mass: 422.495 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27FN4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE CONTAINS AN ILE. NCBI: HTTP://WWW.NCBI.NLM.NIH.GOV/PROTEIN/NP_002728.1

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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: 2.38 Å3/Da / Density % sol: 48.23 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 5.5
Details: 25%(w/v) PEG 3350, 0.1M Bis-Tris, 0.2M magnesium chloride, pH 5.5, VAPOR DIFFUSION, temperature 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 21, 2013
RadiationMonochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.63→77.67 Å / Num. obs: 11659 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 72.57 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 13.8
Reflection shellResolution: 2.61→2.81 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 3.2 / Rsym value: 0.557

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Processing

Software
NameVersionClassification
JDirectordata collection
PHASERphasing
BUSTER2.9.7refinement
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.63→40.77 Å / Cor.coef. Fo:Fc: 0.9472 / Cor.coef. Fo:Fc free: 0.8981 / SU R Cruickshank DPI: 0.792 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2635 553 4.76 %RANDOM
Rwork0.1864 ---
obs0.1898 11609 99.56 %-
Displacement parametersBiso mean: 60.65 Å2
Baniso -1Baniso -2Baniso -3
1--0.0159 Å20 Å2-1.1856 Å2
2---0.9743 Å20 Å2
3---0.9901 Å2
Refine analyzeLuzzati coordinate error obs: 0.334 Å
Refinement stepCycle: LAST / Resolution: 2.63→40.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2579 0 31 40 2650
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012679HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.233631HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d912SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes69HARMONIC2
X-RAY DIFFRACTIONt_gen_planes385HARMONIC5
X-RAY DIFFRACTIONt_it2679HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.65
X-RAY DIFFRACTIONt_other_torsion21.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion327SEMIHARMONIC5
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_contact3058SEMIHARMONIC4
LS refinement shellResolution: 2.63→2.88 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3534 131 4.78 %
Rwork0.2313 2608 -
all0.2369 2739 -
obs--99.56 %

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