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- PDB-7nh5: Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric ... -

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Entry
Database: PDB / ID: 7nh5
TitleCo-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 6
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / Akt2 / Akt3 / covalent-allosteric
Function / homology
Function and homology information


regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / regulation of glycogen biosynthetic process / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / cellular response to rapamycin / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels ...regulation of tRNA methylation / negative regulation of protein maturation / response to insulin-like growth factor stimulus / regulation of glycogen biosynthetic process / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / cellular response to rapamycin / maintenance of protein location in mitochondrion / cellular response to decreased oxygen levels / maternal placenta development / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / potassium channel activator activity / establishment of protein localization to mitochondrion / AKT phosphorylates targets in the nucleus / negative regulation of fatty acid beta-oxidation / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / negative regulation of cilium assembly / cellular response to peptide / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of organ growth / positive regulation of TORC2 signaling / RUNX2 regulates genes involved in cell migration / interleukin-18-mediated signaling pathway / fibroblast migration / response to fluid shear stress / MTOR signalling / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / response to growth factor / positive regulation of glucose metabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RAB GEFs exchange GTP for GDP on RABs / phosphatidylinositol-3,4-bisphosphate binding / negative regulation of leukocyte cell-cell adhesion / positive regulation of protein localization to cell surface / peripheral nervous system myelin maintenance / glycogen biosynthetic process / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / cell migration involved in sprouting angiogenesis / response to growth hormone / positive regulation of fibroblast migration / anoikis / protein serine/threonine kinase inhibitor activity / mammalian oogenesis stage / regulation of postsynapse organization / labyrinthine layer blood vessel development / AKT phosphorylates targets in the cytosol / activation-induced cell death of T cells / TORC2 complex binding / regulation of myelination / response to food / response to UV-A / Regulation of TP53 Activity through Association with Co-factors / KSRP (KHSRP) binds and destabilizes mRNA / execution phase of apoptosis / phosphorylation / negative regulation of macroautophagy / Co-inhibition by CTLA4 / apoptotic mitochondrial changes / negative regulation of cGAS/STING signaling pathway / cellular response to stress / regulation of neuron projection development / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / nitric oxide metabolic process / negative regulation of PERK-mediated unfolded protein response / behavioral response to pain / phosphatidylinositol-3,4,5-trisphosphate binding / TOR signaling / CD28 dependent PI3K/Akt signaling / Regulation of localization of FOXO transcription factors / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of Notch signaling pathway / cellular response to vascular endothelial growth factor stimulus / positive regulation of blood vessel endothelial cell migration / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of fat cell differentiation / positive regulation of G1/S transition of mitotic cell cycle / Mitochondrial unfolded protein response (UPRmt) / positive regulation of glycogen biosynthetic process / vascular endothelial cell response to laminar fluid shear stress / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / 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 / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Regulation of TP53 Activity through Acetylation / striated muscle cell differentiation / positive regulation of endothelial cell proliferation / positive regulation of protein metabolic process
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 / 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 / Mainly Beta
Similarity search - Domain/homology
ACETATE ION / Chem-UC8 / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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)52,3943
Polymers51,7461
Non-polymers6482
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-0 kcal/mol
Surface area17880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.650, 71.410, 91.020
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-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-UC8 / ~{N}-methyl-6-[4-[[4-[2-oxidanylidene-6-(propanoylamino)-3~{H}-benzimidazol-1-yl]piperidin-1-yl]methyl]phenyl]-5-phenyl-pyridine-3-carboxamide


Mass: 588.699 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H36N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.22 Å3/Da / Density % sol: 44.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 18% 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: 0.99998 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: 0.99998 Å / Relative weight: 1
ReflectionResolution: 1.9→43.97 Å / Num. obs: 36972 / % possible obs: 100 % / Redundancy: 13.5 % / Biso Wilson estimate: 47.14 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.048 / Rrim(I) all: 0.05 / Net I/σ(I): 25.85
Reflection shellResolution: 1.9→2 Å / Redundancy: 14.1 % / Rmerge(I) obs: 1.817 / Mean I/σ(I) obs: 1.47 / Num. unique obs: 5186 / CC1/2: 0.679 / Rrim(I) all: 1.885 / % 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: 1.9→43.97 Å / SU ML: 0.2459 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.9603
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2284 1849 5 %
Rwork0.1998 35115 -
obs0.2012 36964 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.66 Å2
Refinement stepCycle: LAST / Resolution: 1.9→43.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3101 0 48 83 3232
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01043309
X-RAY DIFFRACTIONf_angle_d1.08354485
X-RAY DIFFRACTIONf_chiral_restr0.0601470
X-RAY DIFFRACTIONf_plane_restr0.0068571
X-RAY DIFFRACTIONf_dihedral_angle_d25.73781224
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.950.37231400.3482654X-RAY DIFFRACTION99.93
1.95-2.010.31831390.27172653X-RAY DIFFRACTION100
2.01-2.070.27951400.23472660X-RAY DIFFRACTION99.96
2.07-2.150.2771410.2362679X-RAY DIFFRACTION99.96
2.15-2.230.26291420.22592680X-RAY DIFFRACTION100
2.23-2.340.28261400.21512667X-RAY DIFFRACTION100
2.34-2.460.24541410.21882681X-RAY DIFFRACTION99.96
2.46-2.610.27881410.22622681X-RAY DIFFRACTION100
2.61-2.810.30441420.23752696X-RAY DIFFRACTION100
2.81-3.10.25251430.22772709X-RAY DIFFRACTION100
3.1-3.550.24111430.21242719X-RAY DIFFRACTION100
3.55-4.470.19221450.16872763X-RAY DIFFRACTION99.97
4.47-43.970.1851520.17462873X-RAY DIFFRACTION99.8
Refinement TLS params.Method: refined / Origin x: 13.9783080786 Å / Origin y: -11.876787987 Å / Origin z: -15.6412139471 Å
111213212223313233
T0.264305901388 Å2-0.0198194871315 Å2-0.0462863331439 Å2-0.309011713915 Å20.021764176537 Å2--0.284130203076 Å2
L1.78065259052 °20.584361876126 °2-0.0775150443221 °2-1.98663642173 °2-0.000747567389177 °2--1.61470805729 °2
S0.00129235707512 Å °0.0197978234148 Å °-0.0583561508498 Å °-0.0245010965514 Å °-0.0944099535668 Å °-0.0543304654634 Å °-0.0671033347829 Å °0.0101045373212 Å °0.0894143800223 Å °
Refinement TLS groupSelection details: (chain A)

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