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- PDB-7nh4: Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric ... -

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Basic information

Entry
Database: PDB / ID: 7nh4
TitleCo-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / Akt2 / Akt3 / 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
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / 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. ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / 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 / 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
ACETATE ION / Chem-UCE / 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, 4items
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
German Research Foundation (DFG) Germany
CitationJournal: Nat Commun / Year: 2021
Title: Cellular model system to dissect the isoform-selectivity of Akt inhibitors.
Authors: Quambusch, L. / Depta, L. / Landel, I. / Lubeck, M. / Kirschner, T. / Nabert, J. / Uhlenbrock, N. / Weisner, J. / Kostka, M. / Levy, L.M. / Schultz-Fademrecht, C. / Glanemann, F. / Althoff, ...Authors: Quambusch, L. / Depta, L. / Landel, I. / Lubeck, M. / Kirschner, T. / Nabert, J. / Uhlenbrock, N. / Weisner, J. / Kostka, M. / Levy, L.M. / Schultz-Fademrecht, C. / Glanemann, F. / Althoff, K. / Muller, M.P. / Siveke, J.T. / Rauh, D.
History
DepositionFeb 10, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / pdbx_database_proc / pdbx_struct_ref_seq_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _pdbx_struct_ref_seq_depositor_info.db_seq_one_letter_code
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)52,4264
Polymers51,7461
Non-polymers6803
Water27015
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area460 Å2
ΔGint-2 kcal/mol
Surface area17460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.760, 70.950, 91.130
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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 / Mutation: E114A, E115A, E116A
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-UCE / ~{N}-[3-[1-[[4-[5-(hydroxymethyl)-3-phenyl-pyridin-2-yl]phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide


Mass: 561.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H35N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.21 Å3/Da / Density % sol: 44.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 12% v/v PEG 2000 MME, pH 6.5, 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: 0.99999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jun 22, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.3→45.56 Å / Num. obs: 21001 / % possible obs: 99.9 % / Redundancy: 7.4 % / Biso Wilson estimate: 69.37 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rrim(I) all: 0.064 / Net I/σ(I): 15.03
Reflection shellResolution: 2.3→2.4 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.502 / Num. unique obs: 2463 / CC1/2: 0.608 / Rrim(I) all: 1.614 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HHG

6hhg


Resolution: 2.3→45.56 Å / SU ML: 0.3808 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 33.0839
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2457 1047 5 %
Rwork0.2228 19911 -
obs0.2241 20958 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 81.99 Å2
Refinement stepCycle: LAST / Resolution: 2.3→45.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3037 0 50 15 3102
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00233174
X-RAY DIFFRACTIONf_angle_d0.49424298
X-RAY DIFFRACTIONf_chiral_restr0.0399461
X-RAY DIFFRACTIONf_plane_restr0.0026545
X-RAY DIFFRACTIONf_dihedral_angle_d22.33211134
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.420.36771460.33862787X-RAY DIFFRACTION99.9
2.42-2.570.38491480.31762802X-RAY DIFFRACTION99.73
2.57-2.770.33961480.30212805X-RAY DIFFRACTION99.93
2.77-3.050.38761470.28082824X-RAY DIFFRACTION99.73
3.05-3.490.28031490.26112823X-RAY DIFFRACTION99.9
3.49-4.40.21861510.20012874X-RAY DIFFRACTION99.87
4.4-45.560.20711580.19192996X-RAY DIFFRACTION99.87
Refinement TLS params.Method: refined / Origin x: 5.90712760169 Å / Origin y: 3.87002594324 Å / Origin z: 7.27429847286 Å
111213212223313233
T0.528556565227 Å20.0314458799935 Å20.0419729050406 Å2-0.496410679082 Å20.041599118636 Å2--0.480393737651 Å2
L2.06162798946 °2-0.602127901646 °2-0.0434170278665 °2-2.16229879152 °2-0.179319447532 °2--1.68973365244 °2
S-0.074097090459 Å °0.0527799718287 Å °-0.134993241887 Å °-0.0608295447671 Å °0.000103252651825 Å °-0.0392601797828 Å °0.0705735853755 Å °0.145619361771 Å °0.0719879728988 Å °
Refinement TLS groupSelection details: (chain A)

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