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- PDB-6s9w: Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT... -

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Basic information

Entry
Database: PDB / ID: 6s9w
TitleCrystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 16a
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / Akt2 / Akt3 / borussertib / 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 / positive regulation of protein localization to cell surface / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / 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 / activation-induced cell death of T cells / negative regulation of cGAS/STING signaling pathway / 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 / TOR signaling / positive regulation of glycogen biosynthetic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of blood vessel endothelial cell migration / positive regulation of fat cell differentiation / cellular response to vascular endothelial growth factor stimulus / 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 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / positive regulation of endothelial cell proliferation / positive regulation of TORC1 signaling / striated muscle cell differentiation
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Roll / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L1Z / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLandel, I. / Mueller, M.P. / Rauh, D.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
European Regional Development FundEFRE-800400 Germany
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2019
Title: Covalent-Allosteric Inhibitors to Achieve Akt Isoform-Selectivity.
Authors: Quambusch, L. / Landel, I. / Depta, L. / Weisner, J. / Uhlenbrock, N. / Muller, M.P. / Glanemann, F. / Althoff, K. / Siveke, J.T. / Rauh, D.
History
DepositionJul 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,3092
Polymers51,7461
Non-polymers5631
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area20230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.070, 71.030, 91.340
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein RAC-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


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
#2: Chemical ChemComp-L1Z / ~{N}-[3-[1-[[4-(5-methyl-6-oxidanylidene-3-phenyl-1~{H}-pyrazin-2-yl)phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide


Mass: 562.661 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H34N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.2 Å3/Da / Density % sol: 44.08 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 24% v/v PEG 2000 MME, pH 7.0, 3 mg/mL Akt1 (in 25 mM TRIS, 100 mM NaCl, 10% v/v Glycerol, 5 mM DTT, pH 7.5), 1 uL reservoir + 1 uL protein solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.91886 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 20, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91886 Å / Relative weight: 1
ReflectionResolution: 2.3→45.67 Å / Num. obs: 19153 / % possible obs: 91.8 % / Redundancy: 12.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.098 / Rrim(I) all: 0.102 / Net I/σ(I): 15.06
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 12.9 % / Rmerge(I) obs: 1.637 / Mean I/σ(I) obs: 1.62 / Num. unique obs: 2451 / CC1/2: 0.629 / Rrim(I) all: 1.705 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HHG

6hhg


Resolution: 2.3→45.67 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 30.82
RfactorNum. reflection% reflection
Rfree0.2625 957 5 %
Rwork0.2071 --
obs0.2099 19149 91.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 167.36 Å2 / Biso mean: 70.9623 Å2 / Biso min: 28.85 Å2
Refinement stepCycle: final / Resolution: 2.3→45.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3391 0 42 12 3445
Biso mean--59.66 54.26 -
Num. residues----411
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3-2.42130.36811460.28782783100
2.4213-2.57290.34841470.26862783100
2.5729-2.77160.29841020.2681193369
2.7716-3.05040.321480.24182811100
3.0504-3.49170.36291310.2505250489
3.4917-4.39860.22991270.1885239984
4.3986-45.670.21611560.17492979100
Refinement TLS params.Method: refined / Origin x: -13.6844 Å / Origin y: -12.4833 Å / Origin z: 15.0602 Å
111213212223313233
T0.2794 Å20.0162 Å2-0.0366 Å2-0.3448 Å2-0.0304 Å2--0.3188 Å2
L1.6097 °2-0.3338 °2-0.0697 °2-2.0926 °2-0.1139 °2--1.5394 °2
S-0.0424 Å °-0.0353 Å °-0.0853 Å °0.0261 Å °-0.0012 Å °0.0189 Å °0.0155 Å °0.06 Å °0.0575 Å °
Refinement TLS groupSelection details: (chain A)

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