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Yorodumi- PDB-8sbc: Co-structure of Phosphatidylinositol 4,5-bisphosphate 3-kinase ca... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8sbc | ||||||
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Title | Co-structure of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform and brain penetrant inhibitors | ||||||
Components |
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Keywords | TRANSFERASE / lipid kinase / mutant / p85 / niSH2 / brain-penetrant / mTOR | ||||||
Function / homology | Function and homology information perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / positive regulation of focal adhesion disassembly ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / phosphatidylinositol 3-kinase regulator activity / response to butyrate / positive regulation of focal adhesion disassembly / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / cis-Golgi network / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / RHOF GTPase cycle / kinase activator activity / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND2 GTPase cycle / MET activates PI3K/AKT signaling / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of leukocyte migration / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / negative regulation of macroautophagy / 1-phosphatidylinositol-3-kinase activity / RHOB GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / RHOG GTPase cycle / intercalated disc / T cell differentiation / RET signaling / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / RHOA GTPase cycle / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å | ||||||
Authors | Knapp, M.S. / Elling, R.A. / Tang, J. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2023 Title: Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes. Authors: Bonazzi, S. / Gray, A. / Thomsen, N.M. / Biag, J. / Labbe-Giguere, N. / Keaney, E.P. / Malik, H.A. / Sun, Y. / Nunez, J. / Karki, R.G. / Knapp, M. / Elling, R. / Fuller, J. / Pardee, G. / ...Authors: Bonazzi, S. / Gray, A. / Thomsen, N.M. / Biag, J. / Labbe-Giguere, N. / Keaney, E.P. / Malik, H.A. / Sun, Y. / Nunez, J. / Karki, R.G. / Knapp, M. / Elling, R. / Fuller, J. / Pardee, G. / Craig, L. / Capre, K. / Salas, S. / Gorde, A. / Liang, G. / Lubicka, D. / McTighe, S.M. / Goold, C. / Liu, S. / Deng, L. / Hong, J. / Fekete, A. / Stadelmann, P. / Frieauff, W. / Elhajouji, A. / Bauer, D. / Lerchner, A. / Radetich, B. / Furet, P. / Piizzi, G. / Burdette, D. / Wilson, C.J. / Peukert, S. / Hamann, L.G. / Murphy, L.O. / Curtis, D. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8sbc.cif.gz | 514.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8sbc.ent.gz | 418.5 KB | Display | PDB format |
PDBx/mmJSON format | 8sbc.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/sb/8sbc ftp://data.pdbj.org/pub/pdb/validation_reports/sb/8sbc | HTTPS FTP |
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-Related structure data
Related structure data | 8sbjC C: citing same article (ref.) |
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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: 125287.875 Da / Num. of mol.: 1 / Mutation: M232K, L233K, W780K, I800M, V850W, F930V Source method: isolated from a genetically manipulated source Details: Multiple mutations to alter ligand binding characteristics of the ATP binding site M232K, L233K, W780K, I800M, V850W, F930V Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Cell line (production host): Sf21 / Production host: Baculovirus expression vector pFastBac1-HM References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase |
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#2: Protein | Mass: 35142.750 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Details: The difference at 306 is due to remains of cleavage site Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Cell line (production host): Sf21 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P27986 |
#3: Chemical | ChemComp-ZTV / ( |
#4: Chemical | ChemComp-SO4 / |
#5: 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: 2.25 Å3/Da / Density % sol: 45.31 % |
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Crystal grow | Temperature: 303 K / Method: vapor diffusion, hanging drop / pH: 7.2 Details: RESERVOIR SOLUTION : 12%-20% PEG 3350, 0.125M-0.20M KSCN PROTEIN SOLUTION : 20MM TRIS PH 7.2, 200MM NACL, 1% BETAINE, 1% ETHYLENE GLYCOL, 0.02% CHAPS, 5MM DTT, PROTEIN IS 7.4 MG/ML FORMATION ...Details: RESERVOIR SOLUTION : 12%-20% PEG 3350, 0.125M-0.20M KSCN PROTEIN SOLUTION : 20MM TRIS PH 7.2, 200MM NACL, 1% BETAINE, 1% ETHYLENE GLYCOL, 0.02% CHAPS, 5MM DTT, PROTEIN IS 7.4 MG/ML FORMATION METHOD : SOAKING PROTOCOL : SET UP APO XTALS DROPS IN 1:1 RATIO IN 30C, REMARK 280 XTALS GROW OVERNIGHT, THEN ADD 2MM OF STOCK CPD AND INCUBATE FOR A FEW HOURS METHOD : VAPOR DIFFUSION - HANGING DROP TEMPERATURE : 303.0 CRYO PROTOCOL : 20% ETHYLENE GLYCOL PLUS WELL SOLUTION |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 21, 2016 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.3→83.95 Å / Num. obs: 64894 / % possible obs: 99.8 % / Redundancy: 12.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.023 / Rrim(I) all: 0.079 / Χ2: 0.76 / Net I/σ(I): 15.9 / Num. measured all: 823656 |
Reflection shell | Resolution: 2.3→2.42 Å / % possible obs: 99 % / Redundancy: 12 % / Rmerge(I) obs: 1.522 / Num. measured all: 111247 / Num. unique obs: 9289 / CC1/2: 0.844 / Rpim(I) all: 0.454 / Rrim(I) all: 1.59 / Χ2: 0.53 / Net I/σ(I) obs: 1.5 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→83.95 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 36.7 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.3→83.95 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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