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- PDB-8u37: Crystal structure of the catalytic domain of human PKC alpha (D46... -

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Basic information

Entry
Database: PDB / ID: 8u37
TitleCrystal structure of the catalytic domain of human PKC alpha (D463N, V568I, S657E) in complex with NVP-CJL037 at 2.48-A resolution
ComponentsProtein kinase C alpha type
KeywordsTRANSFERASE/INHIBITOR / 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 / 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 / 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
Similarity search - Domain/homology
Chem-V5U / Protein kinase C alpha type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsRomanowski, M.J. / Lam, J. / Visser, M.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.
Authors: Visser, M. / Papillon, J.P.N. / Luzzio, M. / LaMarche, M.J. / Fan, J. / Michael, W. / Wang, D. / Zhang, A. / Straub, C. / Mathieu, S. / Kato, M. / Palermo, M. / Chen, C. / Ramsey, T. / Joud, ...Authors: Visser, M. / Papillon, J.P.N. / Luzzio, M. / LaMarche, M.J. / Fan, J. / Michael, W. / Wang, D. / Zhang, A. / Straub, C. / Mathieu, S. / Kato, M. / Palermo, M. / Chen, C. / Ramsey, T. / Joud, C. / Barrett, R. / Vattay, A. / Guo, R. / Bric, A. / Chung, F. / Liang, G. / Romanowski, M.J. / Lam, J. / Thohan, S. / Atassi, F. / Wylie, A. / Cooke, V.G.
History
DepositionSep 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein kinase C alpha type
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2103
Polymers40,6811
Non-polymers5292
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-7 kcal/mol
Surface area15710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.851, 44.410, 84.789
Angle α, β, γ (deg.)90.000, 114.620, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 40681.414 Da / Num. of mol.: 1 / Fragment: UNP residues 320-672 / Mutation: D463N, V568I, S657E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKCA, PKCA, PRKACA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17252, protein kinase C
#2: Chemical ChemComp-V5U / (6M)-3-amino-N-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-[3-(trifluoromethoxy)pyridin-2-yl]pyrazine-2-carboxamide


Mass: 504.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23F3N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.27 Å3/Da / Density % sol: 45.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Bis-Tris, pH 5.5, 18% PEG3350, 0.2 M magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 14, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.48→52.4 Å / Num. obs: 13022 / % possible obs: 98.7 % / Redundancy: 3.9 % / Biso Wilson estimate: 57.43 Å2 / Rmerge(I) obs: 0.048 / Net I/σ(I): 13.7
Reflection shellResolution: 2.48→2.62 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.372 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 632 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3IW4

3iw4


Resolution: 2.48→38.66 Å / SU ML: 0.3976 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 35.3882
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2578 633 4.88 %
Rwork0.2177 12334 -
obs0.2197 12967 98.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 85.34 Å2
Refinement stepCycle: LAST / Resolution: 2.48→38.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2592 0 37 7 2636
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00772725
X-RAY DIFFRACTIONf_angle_d1.41153690
X-RAY DIFFRACTIONf_chiral_restr0.0749387
X-RAY DIFFRACTIONf_plane_restr0.0124474
X-RAY DIFFRACTIONf_dihedral_angle_d7.3984360
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.48-2.670.4371400.35962423X-RAY DIFFRACTION97.9
2.67-2.940.42671170.32252472X-RAY DIFFRACTION98.55
2.94-3.370.34121330.27082424X-RAY DIFFRACTION98.57
3.37-4.240.20971250.20192485X-RAY DIFFRACTION98.6
4.24-38.660.20761180.17442530X-RAY DIFFRACTION97.75
Refinement TLS params.Method: refined / Origin x: 24.1208186709 Å / Origin y: -0.501735404402 Å / Origin z: 16.4102424511 Å
111213212223313233
T0.481563701162 Å2-0.0287485644631 Å2-0.00602833803717 Å2-0.450903016907 Å20.0203660198482 Å2--0.443671869015 Å2
L0.454283390679 °20.481428272173 °2-0.212438659274 °2-1.60998899491 °2-0.508412707694 °2--1.47359686243 °2
S-0.0501364819541 Å °-0.094150206624 Å °0.0535188932953 Å °0.376115106152 Å °-0.0273064696291 Å °0.0437405713583 Å °-0.112836079716 Å °0.0387218661636 Å °-0.000255149034118 Å °
Refinement TLS groupSelection details: all

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