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Yorodumi- PDB-8uak: Crystal structure of the catalytic domain of human PKC alpha (D46... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8uak | ||||||
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Title | Crystal structure of the catalytic domain of human PKC alpha (D463N, V568I, S657E) in complex with Darovasertib (NVP-LXS196) at 2.82-A resolution | ||||||
Components | Protein kinase C alpha type | ||||||
Keywords | TRANSFERASE/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 / positive regulation of bone resorption / 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 / EGFR Transactivation by Gastrin / RHO GTPases Activate NADPH Oxidases / positive regulation of blood vessel endothelial cell migration / SHC1 events in ERBB2 signaling / post-translational protein modification / positive regulation of endothelial cell proliferation / regulation of mRNA stability / positive regulation of endothelial cell migration / response to interleukin-1 / positive regulation of mitotic cell cycle / ciliary basal body / VEGFR2 mediated cell proliferation / apoptotic signaling pathway / peptidyl-threonine phosphorylation / Signaling by SCF-KIT / mitochondrial membrane / G alpha (z) signalling events / integrin binding / positive regulation of angiogenesis / Inactivation, recovery and regulation of the phototransduction cascade / Ca2+ pathway / peptidyl-serine phosphorylation / angiogenesis / positive regulation of ERK1 and ERK2 cascade / cell adhesion / positive regulation of cell migration / protein kinase activity / intracellular signal transduction / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.82 Å | ||||||
Authors | Romanowski, M.J. / Lam, J. / Visser, M. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8uak.cif.gz | 176.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8uak.ent.gz | 117.4 KB | Display | PDB format |
PDBx/mmJSON format | 8uak.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ua/8uak ftp://data.pdbj.org/pub/pdb/validation_reports/ua/8uak | HTTPS FTP |
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-Related structure data
Related structure data | 8u37C 3iw4S C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 |
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#2: Chemical | ChemComp-W39 / ( |
#3: Water | ChemComp-HOH / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.35 Å3/Da / Density % sol: 47.7 % |
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Crystal grow | Temperature: 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 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Dec 13, 2013 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 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 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB entry 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
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 100.13 Å2 | ||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.82→39.67 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Origin x: 24.5257927661 Å / Origin y: -1.3768270497 Å / Origin z: 16.8208517183 Å
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Refinement TLS group | Selection details: all |