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- PDB-7apj: Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediate... -

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Basic information

Entry
Database: PDB / ID: 7apj
TitleStructure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation
Components
  • NB41
  • RAC-alpha serine/threonine-protein kinase,Non-specific serine/threonine protein kinase,RAC-alpha serine/threonine-protein kinase
KeywordsSIGNALING PROTEIN / kinase / autoinhibition / lipid / membrane / PIP3 / Akt
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 / protein serine/threonine kinase activity => GO:0004674 / cellular response to decreased oxygen levels ...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 / protein serine/threonine kinase activity => GO:0004674 / 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 neuron differentiation / 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
Similarity search - Function
Serine/threonine-protein kinase RAC alpha / 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. ...Serine/threonine-protein kinase RAC alpha / 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
Non-specific serine/threonine protein kinase / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
Danio rerio (zebrafish)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsTruebestein, L. / Hornegger, H. / Leonard, T.A.
Funding support Austria, 4items
OrganizationGrant numberCountry
Austrian Science FundP28135 Austria
Austrian Science FundP30584 Austria
Austrian Science FundP33066 Austria
Austrian Science FundT915 Austria
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2021
Title: Structure of autoinhibited Akt1 reveals mechanism of PIP 3 -mediated activation.
Authors: Truebestein, L. / Hornegger, H. / Anrather, D. / Hartl, M. / Fleming, K.D. / Stariha, J.T.B. / Pardon, E. / Steyaert, J. / Burke, J.E. / Leonard, T.A.
History
DepositionOct 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 25, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 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,Non-specific serine/threonine protein kinase,RAC-alpha serine/threonine-protein kinase
B: NB41


Theoretical massNumber of molelcules
Total (without water)65,2922
Polymers65,2922
Non-polymers00
Water2,936163
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance, Binding affinity of 16 nM determined by SPR.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1460 Å2
ΔGint-6 kcal/mol
Surface area26150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.008, 72.197, 120.173
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,Non-specific serine/threonine protein kinase,RAC-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 51408.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Danio rerio (zebrafish)
Gene: AKT1, PKB, RAC, akt1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, UniProt: M4MD44, non-specific serine/threonine protein kinase
#2: Antibody NB41


Mass: 13883.611 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 163 / Source method: isolated from a natural source / Formula: H2O

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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: 2.33 Å3/Da / Density % sol: 47.3 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 200 mM malonate, pH 5.0, 16% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Sep 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 2.05→45.6 Å / Num. obs: 38951 / % possible obs: 99.8 % / Redundancy: 8.1 % / Biso Wilson estimate: 39.18 Å2 / CC1/2: 0.998 / Net I/σ(I): 9.7
Reflection shellResolution: 2.05→2.13 Å / Redundancy: 7.9 % / Num. unique obs: 3750 / CC1/2: 0.658 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PHENIX1.18.2_3874refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1UNP, 4EKK, 3EZJ

1unp

4ekk

3ezj


Resolution: 2.05→38.55 Å / SU ML: 0.2714 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.9005
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2519 1951 5.02 %
Rwork0.211 36907 -
obs0.2129 38858 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.66 Å2
Refinement stepCycle: LAST / Resolution: 2.05→38.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4096 0 0 163 4259
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00244187
X-RAY DIFFRACTIONf_angle_d0.50735646
X-RAY DIFFRACTIONf_chiral_restr0.0419602
X-RAY DIFFRACTIONf_plane_restr0.0034725
X-RAY DIFFRACTIONf_dihedral_angle_d20.76411576
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.10.35931230.33052577X-RAY DIFFRACTION98.32
2.1-2.160.36521560.31592559X-RAY DIFFRACTION99.96
2.16-2.220.33461500.28842597X-RAY DIFFRACTION100
2.22-2.290.25851460.26982593X-RAY DIFFRACTION99.89
2.29-2.380.31521390.2632597X-RAY DIFFRACTION99.85
2.38-2.470.31221330.24942626X-RAY DIFFRACTION99.96
2.47-2.580.27561440.23562631X-RAY DIFFRACTION99.78
2.58-2.720.34091520.23422603X-RAY DIFFRACTION99.93
2.72-2.890.24951340.2252626X-RAY DIFFRACTION99.96
2.89-3.110.24841180.22442644X-RAY DIFFRACTION99.93
3.11-3.430.28121240.21022682X-RAY DIFFRACTION100
3.43-3.920.25171350.18612672X-RAY DIFFRACTION99.89
3.92-4.940.18971240.16262709X-RAY DIFFRACTION99.96
4.94-38.550.21081730.19912791X-RAY DIFFRACTION99.3
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.84328345163-0.02121352834791.289282269793.306442037350.9405258249075.305020501180.01008436299640.11666540090.476719573315-0.116740046866-0.02619888216520.0245393662677-0.344448295348-0.0693536987929-0.003851530913810.4866678992890.01741793776670.03306472500930.2148220727170.0005542485741270.2600699791232.75468810133-11.16044207576.78033437336
21.067438810750.14030638584-0.205320546910.9627167155270.5887312242350.655133650203-0.08716508820280.3260426796780.420536980258-0.1472953790650.227827063676-0.0636969521747-0.233919558560.256062393487-0.151144926090.606355699485-0.09052480362970.03668379213520.6388334458950.05493751055440.48913911756110.38809981135.68490119929-7.48153315781
35.209533222760.369722894416-3.064428325932.57900142840.4267699381564.64226842411-0.0922977915111.06806713098-0.189634495333-0.5092950838530.102922827382-0.543441568989-0.1872335874530.4375981571270.00842585163050.571832729804-0.07167142884820.06001052817360.56170437367-0.009824150291440.48275128651214.380694924122.55461657178.8061294848
41.35287560380.321036001755-0.286619647954.46622450834-0.1308146077222.54578758433-0.01628140192050.141138281336-0.0773358435141-0.179594979868-0.00373752227336-0.1596607644430.07607369538610.06284954689120.04472207275470.279366639649-0.00243911113612-0.002899744149080.244339951742-0.0140728927740.2220622883612.9920096816815.57936356423.1495561856
52.83659872356-1.585327857722.198930075747.35879520265-5.584438336824.63160235164-0.37368604418-0.296021257388-0.430221946082-0.383521959410.0632228424982-0.1905559790761.433242454180.1256051540470.48247482270.8010426404880.195527917840.140283208730.4980661769230.09394468278540.427237818892-0.3537247971892.32203038047-45.5410963455
69.64769709269-0.9854509145520.5110920951912.710591039322.668707714772.981804621630.049545504637-0.69789388929-1.160029533760.0157875870078-0.2693717575780.1261622248261.631340830780.00825219089043-0.001301667639070.7393600070380.1179814081120.09073292250540.5912159984060.2315911078410.555087217424-4.73071815235-3.12221891464-27.7617596416
77.54136618556-0.439359347678-4.422178672564.80573681812-0.09559557517256.5840777430.0966704849436-0.566189697829-0.1545186092070.000722214890074-0.435448747187-0.5771158109-0.543326378411.532004224150.3631270914040.495945650956-0.00432455955694-0.009893512906710.8070854067950.2578782616710.3561979200022.716234613339.71394257141-35.2010037142
85.327228849373.70965420226-4.717980561923.74664126825-3.470467384354.203028295120.167234020711-1.134188038240.3295148586150.918376377521-0.02094923544970.0378274863147-1.81743841580.2386087561060.2846215228880.887059997542-0.0568281055358-0.08150693733610.7115293729020.1654342289550.383800532375-3.2991946946616.5220121479-36.2168179331
93.475938878660.102131628777-0.7335769254318.83964717264-1.618510654732.15164662316-0.260599598263-0.409474042559-0.2264855697020.5237631223040.08068151831950.5175724396450.2075643391-0.2531063586680.3213533845370.5277215277910.0233173686370.03946432181050.4818145879340.1358640544190.36369653798-7.085904177675.2863306782-39.0184642367
100.768309260251-1.247080197572.395185635584.82198233875-5.341325809638.33199452786-0.0576846444898-0.686383378145-0.1975088492050.00129614756199-0.338917113787-0.4012526271380.1172634520721.245001613390.4488973722960.515467890720.1057798968990.06451014377840.7265906863330.1753789882220.3597833316353.189813854610.4112577028-44.6839378162
114.0817655268-2.687360599781.017271934162.77938546643-2.333351178922.98609683052-0.2674153133710.3094396997030.04656355713650.57455257863-0.597499687082-0.8168061175-0.6482184046561.287469296120.7024439891280.5446554529080.0450050591350.04235068216440.9640504507420.4459599520030.547929982485.71225560993.48554306407-25.948654525
121.53610465025-0.249745133691.522613522666.09120994585-3.575871915743.34577294206-0.48071953296-0.556645970168-0.832610030861-0.636199155291-0.289712436052-0.3874050887891.410984495051.295576581770.3393541387170.5444825021940.3409171502850.2502963311950.9510451392130.405657936710.5657732799757.470089676175.58313869249-45.9842260172
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 3 through 92 )AA3 - 921 - 90
22chain 'A' and (resid 93 through 161 )AA93 - 16191 - 149
33chain 'A' and (resid 162 through 239 )AA162 - 239150 - 210
44chain 'A' and (resid 240 through 432 )AA240 - 432211 - 385
55chain 'B' and (resid 3 through 24 )BB3 - 241 - 22
66chain 'B' and (resid 25 through 33 )BB25 - 3323 - 31
77chain 'B' and (resid 34 through 56 )BB34 - 5632 - 54
88chain 'B' and (resid 57 through 63 )BB57 - 6355 - 61
99chain 'B' and (resid 64 through 82 )BB64 - 8262 - 80
1010chain 'B' and (resid 83 through 96 )BB83 - 9681 - 94
1111chain 'B' and (resid 97 through 102 )BB97 - 10295 - 100
1212chain 'B' and (resid 103 through 119 )BB103 - 119101 - 117

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