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Yorodumi- PDB-6hhj: Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT... -
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-Basic information
Entry | Database: PDB / ID: 6hhj | |||||||||
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Title | Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 24b | |||||||||
Components | RAC-alpha serine/threonine-protein kinase | |||||||||
Keywords | TRANSFERASE / Akt1 / covalent-allosteric | |||||||||
Function / homology | Function and homology information glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / maternal placenta development / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / negative regulation of fatty acid beta-oxidation / AKT phosphorylates targets in the nucleus / regulation of glycogen biosynthetic process / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / MTOR signalling / fibroblast migration / interleukin-18-mediated signaling pathway / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein serine/threonine kinase activity / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / positive regulation of endodeoxyribonuclease activity / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of protein localization to cell surface / protein serine/threonine kinase inhibitor activity / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / sphingosine-1-phosphate receptor signaling pathway / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / glycogen biosynthetic process / AKT phosphorylates targets in the cytosol / labyrinthine layer blood vessel development / execution phase of apoptosis / response to food / response to UV-A / regulation of myelination / regulation of postsynapse organization / regulation of neuron projection development / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / mammalian oogenesis stage / negative regulation of macroautophagy / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / activation-induced cell death of T cells / negative regulation of Notch signaling pathway / behavioral response to pain / non-canonical NF-kappaB signal transduction / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / apoptotic mitochondrial changes / CD28 dependent PI3K/Akt signaling / phosphatidylinositol-3,4,5-trisphosphate binding / Regulation of localization of FOXO transcription factors / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of glycogen biosynthetic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / TOR signaling / Activation of BAD and translocation to mitochondria / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / positive regulation of fat cell differentiation / canonical NF-kappaB signal transduction / positive regulation of G1/S transition of mitotic cell cycle / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / positive regulation of lipid biosynthetic process / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin A:Cdk2-associated events at S phase entry / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / lipopolysaccharide-mediated signaling pathway / regulation of cell migration / negative regulation of protein ubiquitination / cellular response to epidermal growth factor stimulus / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / positive regulation of endothelial cell proliferation / striated muscle cell differentiation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å | |||||||||
Authors | Landel, I. / Weisner, J. / Mueller, M.P. / Scheinpflug, R. / Rauh, D. | |||||||||
Funding support | Germany, 2items
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Citation | Journal: Chem Sci / Year: 2019 Title: Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt. Authors: Uhlenbrock, N. / Smith, S. / Weisner, J. / Landel, I. / Lindemann, M. / Le, T.A. / Hardick, J. / Gontla, R. / Scheinpflug, R. / Czodrowski, P. / Janning, P. / Depta, L. / Quambusch, L. / ...Authors: Uhlenbrock, N. / Smith, S. / Weisner, J. / Landel, I. / Lindemann, M. / Le, T.A. / Hardick, J. / Gontla, R. / Scheinpflug, R. / Czodrowski, P. / Janning, P. / Depta, L. / Quambusch, L. / Muller, M.P. / Engels, B. / Rauh, D. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6hhj.cif.gz | 185.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6hhj.ent.gz | 147.1 KB | Display | PDB format |
PDBx/mmJSON format | 6hhj.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6hhj_validation.pdf.gz | 701.6 KB | Display | wwPDB validaton report |
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Full document | 6hhj_full_validation.pdf.gz | 707.6 KB | Display | |
Data in XML | 6hhj_validation.xml.gz | 18.1 KB | Display | |
Data in CIF | 6hhj_validation.cif.gz | 25 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/hh/6hhj ftp://data.pdbj.org/pub/pdb/validation_reports/hh/6hhj | HTTPS FTP |
-Related structure data
Related structure data | 6hhgSC 6hhhC 6hhiC S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 51746.035 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P31749, non-specific serine/threonine protein kinase |
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#2: Chemical | ChemComp-G4H / ~{ |
#3: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.2 Å3/Da / Density % sol: 44.02 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 15 % v/v PEG 2000 MME, pH 7.5, 3 mg/mL Akt1 (in 25 mM TRIS, 100 mM NaCl, 10 % Glycerol, 5 mM DTT, pH 7.5), 1ul reservoir + 1ul protein solution |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00000482378 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2018 |
Radiation | Monochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.00000482378 Å / Relative weight: 1 |
Reflection | Resolution: 2.3→43.812 Å / Num. obs: 20861 / % possible obs: 99.9 % / Redundancy: 7.2 % / CC1/2: 0.994 / Rmerge(I) obs: 0.185 / Rrim(I) all: 0.201 / Net I/σ(I): 7.81 |
Reflection shell | Resolution: 2.3→2.4 Å / Redundancy: 7.1 % / Rmerge(I) obs: 1.075 / Mean I/σ(I) obs: 1.37 / Num. unique obs: 2443 / CC1/2: 0.708 / Rrim(I) all: 1.103 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 6HHG Resolution: 2.3→43.812 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 27.01
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.3→43.812 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: 13.5227 Å / Origin y: -12.4667 Å / Origin z: -15.2227 Å
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Refinement TLS group | Selection details: (chain A) |