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- PDB-9c1w: Structure of AKT2 with compound 3 -

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Basic information

Entry
Database: PDB / ID: 9c1w
TitleStructure of AKT2 with compound 3
ComponentsRAC-beta serine/threonine-protein kinase
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / Kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


retinal rod cell apoptotic process / PDE3B signalling / cellular response to high light intensity / Inhibition of TSC complex formation by PKB / positive regulation of cap-dependent translational initiation / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / Activation of AKT2 / AKT phosphorylates targets in the nucleus ...retinal rod cell apoptotic process / PDE3B signalling / cellular response to high light intensity / Inhibition of TSC complex formation by PKB / positive regulation of cap-dependent translational initiation / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / Activation of AKT2 / AKT phosphorylates targets in the nucleus / RUNX2 regulates genes involved in cell migration / positive regulation of fatty acid beta-oxidation / mammary gland epithelial cell differentiation / positive regulation of glucose metabolic process / RAB GEFs exchange GTP for GDP on RABs / peripheral nervous system myelin maintenance / glycogen biosynthetic process / AKT phosphorylates targets in the cytosol / Regulation of TP53 Activity through Association with Co-factors / positive regulation of cell motility / Co-inhibition by CTLA4 / Constitutive Signaling by AKT1 E17K in Cancer / fat cell differentiation / negative regulation of PERK-mediated unfolded protein response / Regulation of MITF-M-dependent genes involved in pigmentation / Regulation of localization of FOXO transcription factors / positive regulation of protein targeting to membrane / CD28 dependent PI3K/Akt signaling / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of glycogen biosynthetic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / Regulation of TP53 Activity through Acetylation / FLT3 Signaling / Downregulation of ERBB2:ERBB3 signaling / regulation of cell migration / molecular function activator activity / protein localization to plasma membrane / VEGFR2 mediated vascular permeability / positive regulation of D-glucose import / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / Deactivation of the beta-catenin transactivating complex / protein modification process / ruffle membrane / Regulation of PTEN stability and activity / cellular response to insulin stimulus / glucose metabolic process / KEAP1-NFE2L2 pathway / G beta:gamma signalling through PI3Kgamma / Regulation of TP53 Degradation / insulin receptor signaling pathway / PIP3 activates AKT signaling / cell cortex / eukaryotic translation initiation factor 2alpha kinase activity / early endosome / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / regulation of cell cycle / protein stabilization / intracellular signal transduction / positive regulation of cell migration / protein serine kinase activity / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / signal transduction / nucleoplasm / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Protein Kinase B beta, 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 beta, 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
: / RAC-beta serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsCraven, G.B. / Ma, X. / Taunton, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Tobacco-Related Disease Research Program (TRDRP)T32FT4880 United States
CitationJournal: Nature / Year: 2025
Title: Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation.
Authors: Craven, G.B. / Chu, H. / Sun, J.D. / Carelli, J.D. / Coyne, B. / Chen, H. / Chen, Y. / Ma, X. / Das, S. / Kong, W. / Zajdlik, A.D. / Yang, K.S. / Reisberg, S.H. / Thompson, P.A. / Lipford, J.R. / Taunton, J.
History
DepositionMay 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Jan 8, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)52,6628
Polymers51,7491
Non-polymers9137
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.140, 76.140, 153.310
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

#1: Protein RAC-beta serine/threonine-protein kinase / Protein kinase Akt-2 / Protein kinase B beta / PKB beta / RAC protein kinase beta / RAC-PK-beta


Mass: 51749.109 Da / Num. of mol.: 1 / Mutation: P115A, G116A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31751, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-XOO / 4-{2-[({4-[(2P)-2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}methyl)amino]ethyl}-2-hydroxybenzaldehyde


Mass: 540.614 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.8 Å3/Da / Density % sol: 56.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1 M HEPES pH 7.5, 20 % w/v PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 0.99987 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 8, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 2→27.7 Å / Num. obs: 35510 / % possible obs: 99.91 % / Redundancy: 19.9 % / Biso Wilson estimate: 43.57 Å2 / CC1/2: 0.999 / Net I/σ(I): 17.1
Reflection shellResolution: 2→2.071 Å / Num. unique obs: 3474 / CC1/2: 0.631

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Processing

Software
NameVersionClassification
PHASERphasing
PHENIX1.20.1_4487refinement
xia2data reduction
xia2data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→27.7 Å / SU ML: 0.2286 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.1748
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2416 1699 4.78 %
Rwork0.2048 33809 -
obs0.2066 35508 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.92 Å2
Refinement stepCycle: LAST / Resolution: 2→27.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3191 0 65 133 3389
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00833329
X-RAY DIFFRACTIONf_angle_d0.94014479
X-RAY DIFFRACTIONf_chiral_restr0.0515472
X-RAY DIFFRACTIONf_plane_restr0.0072567
X-RAY DIFFRACTIONf_dihedral_angle_d16.30371282
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.060.28861390.27032775X-RAY DIFFRACTION99.97
2.06-2.130.30221580.25112735X-RAY DIFFRACTION100
2.13-2.20.31771540.25142769X-RAY DIFFRACTION100
2.2-2.290.23371190.21392791X-RAY DIFFRACTION100
2.29-2.390.26671670.22642750X-RAY DIFFRACTION100
2.39-2.520.29351080.21312832X-RAY DIFFRACTION99.93
2.52-2.680.30341300.24692792X-RAY DIFFRACTION100
2.68-2.880.28871460.22122822X-RAY DIFFRACTION100
2.88-3.170.25851330.23482839X-RAY DIFFRACTION100
3.17-3.630.25461300.20642854X-RAY DIFFRACTION100
3.63-4.570.21621630.17912841X-RAY DIFFRACTION100
4.57-27.70.2071520.18533009X-RAY DIFFRACTION99.84

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