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

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Basic information

Entry
Database: PDB / ID: 8uak
TitleCrystal structure of the catalytic domain of human PKC alpha (D463N, V568I, S657E) in complex with Darovasertib (NVP-LXS196) at 2.82-A resolution
ComponentsProtein kinase C alpha type
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / complex / Darovasertib / NVP-LXS196 / NVP-CJL037 / 8u37 / 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 / ROBO receptors bind AKAP5 / WNT5A-dependent internalization of FZD4 / Acetylcholine regulates insulin secretion / 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 / RET signaling / positive regulation of cell adhesion / 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 / positive regulation of endothelial cell migration / SHC1 events in ERBB2 signaling / positive regulation of mitotic cell cycle / response to interleukin-1 / 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 / zinc ion binding / extracellular exosome / nucleoplasm / ATP binding / plasma membrane / cytoplasm / cytosol
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 / 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-W39 / Protein kinase C alpha type
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.82 Å
AuthorsRomanowski, M.J. / Lam, J. / Visser, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
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 21, 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

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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)41,1542
Polymers40,6811
Non-polymers4721
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.818, 44.532, 85.691
Angle α, β, γ (deg.)90.000, 114.040, 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-W39 / (6M)-3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide


Mass: 472.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23F3N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.35 Å3/Da / Density % sol: 47.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 21 mg/mL protein in 50 mM imidazole, 200 mM sodium chloride, 2 mM TCEP, 1 mM NAF, 1% glycerol, pH 8.0 against 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 200K / Detector: PIXEL / Date: Dec 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.82→53.2 Å / Num. obs: 9293 / % possible obs: 99.3 % / Redundancy: 3.9 % / Biso Wilson estimate: 81.66 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.062 / Net I/σ(I): 13.3
Reflection shellResolution: 2.82→2.83 Å / Rmerge(I) obs: 0.628 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 95 / CC1/2: 0.743

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Processing

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

3iw4


Resolution: 2.82→39.67 Å / SU ML: 0.3518 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 32.2328
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.243 439 4.73 %
Rwork0.206 8842 -
obs0.2077 9281 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 100.13 Å2
Refinement stepCycle: LAST / Resolution: 2.82→39.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2586 0 34 1 2621
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00642713
X-RAY DIFFRACTIONf_angle_d1.33873675
X-RAY DIFFRACTIONf_chiral_restr0.08388
X-RAY DIFFRACTIONf_plane_restr0.0092470
X-RAY DIFFRACTIONf_dihedral_angle_d8.61363
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.82-3.230.34121400.2972927X-RAY DIFFRACTION99.68
3.23-4.070.26871600.22782910X-RAY DIFFRACTION99.29
4.07-39.670.2151390.183005X-RAY DIFFRACTION98.71
Refinement TLS params.Method: refined / Origin x: 24.5257927661 Å / Origin y: -1.3768270497 Å / Origin z: 16.8208517183 Å
111213212223313233
T0.522912297467 Å2-0.0719850500068 Å2-0.0750044265711 Å2-0.502503993745 Å20.0396635125799 Å2--0.522966795817 Å2
L2.00845510847 °20.127980728643 °2-1.12803045892 °2-2.81738015615 °2-0.66326141066 °2--3.84829121058 °2
S0.111719782758 Å °-0.211473089151 Å °0.024450117267 Å °0.522822697613 Å °-0.203137513929 Å °0.0810323334368 Å °-0.360016625475 Å °0.257650664759 Å °-0.00887182968048 Å °
Refinement TLS groupSelection details: all

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