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- PDB-3iw4: Crystal structure of PKC alpha in complex with NVP-AEB071 -

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Basic information

Entry
Database: PDB / ID: 3iw4
TitleCrystal structure of PKC alpha in complex with NVP-AEB071
ComponentsProtein kinase C alpha type
KeywordsTRANSFERASE / kinase / ATP-binding / Cell membrane / Membrane / Metal-binding / Nucleotide-binding / Phorbol-ester binding / Phosphoprotein / Serine/threonine-protein kinase / Zinc-finger
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 / calcium,diacylglycerol-dependent serine/threonine kinase activity / histone H3T6 kinase activity / diacylglycerol binding / HuR (ELAVL1) binds and stabilizes mRNA / Depolymerization of the Nuclear Lamina ...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 / calcium,diacylglycerol-dependent serine/threonine kinase activity / histone H3T6 kinase activity / diacylglycerol binding / HuR (ELAVL1) binds and stabilizes mRNA / Depolymerization of the Nuclear Lamina / Trafficking of GluR2-containing AMPA receptors / ROBO receptors bind AKAP5 / WNT5A-dependent internalization of FZD4 / protein kinase C / Acetylcholine regulates insulin secretion / diacylglycerol-dependent serine/threonine kinase activity / negative regulation of glial cell apoptotic process / 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 / Regulation of KIT signaling / Syndecan interactions / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cardiac muscle hypertrophy / 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 / post-translational protein modification / positive regulation of endothelial cell migration / SHC1 events in ERBB2 signaling / positive regulation of cell adhesion / response to interleukin-1 / positive regulation of mitotic cell cycle / ciliary basal body / VEGFR2 mediated cell proliferation / apoptotic signaling pathway / peptidyl-threonine phosphorylation / mitochondrial membrane / Signaling by SCF-KIT / positive regulation of insulin secretion / 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 / 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. / Protein kinase C conserved region 2 (CalB) / C2 domain ...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. / Protein kinase C conserved region 2 (CalB) / C2 domain / 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-LW4 / Protein kinase C alpha type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsStark, W. / Rummel, G. / Strauss, A. / Cowan-Jacob, S.W.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes
Authors: Wagner, J. / von Matt, P. / Sedrani, R. / Albert, R. / Cooke, N. / Ehrhardt, C. / Geiser, M. / Rummel, G. / Stark, W. / Strauss, A. / Cowan-Jacob, S.W. / Beerli, C. / Weckbecker, G. / ...Authors: Wagner, J. / von Matt, P. / Sedrani, R. / Albert, R. / Cooke, N. / Ehrhardt, C. / Geiser, M. / Rummel, G. / Stark, W. / Strauss, A. / Cowan-Jacob, S.W. / Beerli, C. / Weckbecker, G. / Evenou, J.P. / Zenke, G. / Cottens, S.
History
DepositionSep 2, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Nov 10, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / 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 / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)126,0306
Polymers124,7143
Non-polymers1,3153
Water82946
1
A: Protein kinase C alpha type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0102
Polymers41,5711
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Protein kinase C alpha type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0102
Polymers41,5711
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Protein kinase C alpha type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,0102
Polymers41,5711
Non-polymers4381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.868, 100.669, 251.335
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Protein kinase C alpha type / PKC-alpha / PKC-A


Mass: 41571.387 Da / Num. of mol.: 3 / Fragment: kinase domain, UNP residues 320-672
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCA, PKCA, PRKACA / Plasmid: pXI525e / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17252, protein kinase C
#2: Chemical ChemComp-LW4 / 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]-1H-pyrrole-2,5-dione


Mass: 438.481 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C25H22N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.22 Å3/Da / Density % sol: 44.72 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 5.1
Details: protein solution: 12mg/mL in 0.2M NaCl, 0.05M imidazole, pH8.0, 2mM TCEP, 1mM NAF, 2% glycerol, reservoir solution: 1mL 22% polyethyleneglycol 3350, 0.2M di-ammonium-hydrogen citrate, pH5.1, ...Details: protein solution: 12mg/mL in 0.2M NaCl, 0.05M imidazole, pH8.0, 2mM TCEP, 1mM NAF, 2% glycerol, reservoir solution: 1mL 22% polyethyleneglycol 3350, 0.2M di-ammonium-hydrogen citrate, pH5.1, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9788 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 1, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9788 Å / Relative weight: 1
ReflectionResolution: 2.8→100 Å / Num. all: 28331 / Num. obs: 28331 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4.5 % / Biso Wilson estimate: 45.933 Å2 / Rmerge(I) obs: 0.138 / Net I/σ(I): 9.21
Reflection shellResolution: 2.8→2.92 Å / Rmerge(I) obs: 0.664 / Mean I/σ(I) obs: 2.3 / Num. measured obs: 13561 / Num. unique obs: 3185 / % possible all: 98.5

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
MAR345data collection
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.8→64.42 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.876 / WRfactor Rfree: 0.247 / WRfactor Rwork: 0.171 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.808 / SU B: 37.86 / SU ML: 0.335 / SU R Cruickshank DPI: 0.32 / SU Rfree: 0.439 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R Free: 0.436 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES: RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.27703 1417 5 %RANDOM
Rwork0.19209 ---
obs0.19625 26913 99.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 94.52 Å2 / Biso mean: 39.781 Å2 / Biso min: 8.48 Å2
Baniso -1Baniso -2Baniso -3
1--1.33 Å20 Å20 Å2
2--1.46 Å20 Å2
3----0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.8→64.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8051 0 99 46 8196
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0228366
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4241.98811315
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5175986
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.03924.364401
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.11415.0311460
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.0621542
X-RAY DIFFRACTIONr_chiral_restr0.0880.21178
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216361
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.13624946
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.23338005
X-RAY DIFFRACTIONr_scbond_it3.5314.53420
X-RAY DIFFRACTIONr_scangle_it5.38363310
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 101 -
Rwork0.251 1927 -
all-2028 -
obs--98.59 %
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)
11.1844-0.16690.33230.48060.02970.5645-0.0035-0.15440.35270.0425-0.07810.0170.0502-0.03860.08160.02040.00090.00630.0501-0.05470.12690.37626.1157.184
20.51890.09720.02682.1733-0.68170.65340.07320.08530.0845-0.4984-0.12250.00930.1775-0.00250.04930.14940.05620.03970.06560.03650.0578-20.82719.75124.77
30.74280.0250.11950.40130.27021.0277-0.0014-0.1128-0.09530.0431-0.0286-0.02330.06480.01930.02990.03620.00440.01380.07820.06220.0531-21.61868.57315.207
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A331 - 669
2X-RAY DIFFRACTION2B332 - 666
3X-RAY DIFFRACTION3C330 - 670

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