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- PDB-8q61: Co-crystal structure of human AKT2 with compound 3 -

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Basic information

Entry
Database: PDB / ID: 8q61
TitleCo-crystal structure of human AKT2 with compound 3
ComponentsRAC-beta serine/threonine-protein kinase
KeywordsTRANSFERASE / Protein Kinase 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 / positive regulation of glucose metabolic process / positive regulation of fatty acid beta-oxidation / RUNX2 regulates genes involved in cell migration / mammary gland epithelial cell differentiation / RAB GEFs exchange GTP for GDP on RABs / glycogen biosynthetic process / peripheral nervous system myelin maintenance / AKT phosphorylates targets in the cytosol / positive regulation of cell motility / Regulation of TP53 Activity through Association with Co-factors / 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 / CD28 dependent PI3K/Akt signaling / positive regulation of protein targeting to membrane / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / 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 / Downregulation of ERBB2:ERBB3 signaling / Regulation of TP53 Activity through Acetylation / FLT3 Signaling / Deactivation of the beta-catenin transactivating complex / regulation of cell migration / molecular function activator activity / VEGFR2 mediated vascular permeability / protein localization to plasma membrane / positive regulation of D-glucose import / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / protein modification process / Regulation of PTEN stability and activity / ruffle membrane / cellular response to insulin stimulus / glucose metabolic process / KEAP1-NFE2L2 pathway / Regulation of TP53 Degradation / G beta:gamma signalling through PI3Kgamma / insulin receptor signaling pathway / PIP3 activates AKT signaling / cell cortex / early endosome / 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 / 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 beta, 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
Chem-K06 / PHOSPHATE ION / RAC-beta serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.32 Å
AuthorsHarrison, T. / Barker, O.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other government United Kingdom
CitationJournal: Sci Rep / Year: 2022
Title: Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development.
Authors: Page, N. / Wappett, M. / O'Dowd, C.R. / O'Rourke, M. / Gavory, G. / Zhang, L. / Rountree, J.S.S. / Jordan, L. / Barker, O. / Gibson, H. / Boyd, C. / Feutren-Burton, S. / McLean, E. / Trevitt, G. / Harrison, T.
History
DepositionAug 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release

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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)56,9917
Polymers55,9751
Non-polymers1,0166
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint-5 kcal/mol
Surface area20090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.667, 113.885, 73.048
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein RAC-beta serine/threonine-protein kinase


Mass: 55974.785 Da / Num. of mol.: 1 / Mutation: N2D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT2 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P31751

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Non-polymers , 5 types, 152 molecules

#2: Chemical ChemComp-K06 / 6-[4-(1-azanyl-3-methyl-3-oxidanyl-cyclobutyl)phenyl]-7-phenyl-1-propyl-pyrido[2,3-b][1,4]oxazin-2-one


Mass: 443.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.37 Å3/Da / Density % sol: 48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES, 1.5 M NaH2PO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00004 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 2.32→61.49 Å / Num. obs: 22371 / % possible obs: 99.58 % / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Biso Wilson estimate: 48.372 Å2 / Rmerge(I) obs: 0.057 / Net I/σ(I): 0
Reflection shellResolution: 2.32→2.57 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.441 / Num. unique obs: 1613 / % possible all: 99.5

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
MERLOTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.32→61.49 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.909 / SU B: 13.585 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.298 / ESU R Free: 0.24 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2634 1187 5 %RANDOM
Rwork0.20912 ---
obs0.21167 22371 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 48.372 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å2-0 Å2-0 Å2
2---1.08 Å20 Å2
3---0.96 Å2
Refinement stepCycle: LAST / Resolution: 2.32→61.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3152 0 66 146 3364
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193237
X-RAY DIFFRACTIONr_bond_other_d0.0040.023110
X-RAY DIFFRACTIONr_angle_refined_deg1.5471.9854368
X-RAY DIFFRACTIONr_angle_other_deg1.21237129
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5515380
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.36622.603146
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.37415.052573
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5411527
X-RAY DIFFRACTIONr_chiral_restr0.0870.2469
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213517
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02755
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5723.4731534
X-RAY DIFFRACTIONr_mcbond_other2.5693.4741533
X-RAY DIFFRACTIONr_mcangle_it3.9645.8331909
X-RAY DIFFRACTIONr_mcangle_other3.9655.8331910
X-RAY DIFFRACTIONr_scbond_it3.8064.1531703
X-RAY DIFFRACTIONr_scbond_other3.8024.1531703
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.6966.7512458
X-RAY DIFFRACTIONr_long_range_B_refined7.91631.3393449
X-RAY DIFFRACTIONr_long_range_B_other7.931.1423428
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.32→2.38 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.404 84 -
Rwork0.316 1613 -
obs--98.84 %
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)
10.7561-0.1579-0.18425.17193.08744.2387-0.0830.07920.17180.14640.02570.202-0.0807-0.13070.05730.15050.0422-0.01120.1495-0.00230.1321-1.782-13.807-16.746
24.58191.09250.32635.3309-1.28994.8814-0.02860.0331-0.2624-0.0824-0.0217-0.72630.2770.66190.05030.1128-0.0081-0.01230.13990.00410.11191.9831.5457.095
32.1595-0.26570.61252.61170.39064.32990.0371-0.0116-0.04860.0191-0.08360.1181-0.074-0.15890.04640.0896-0.03290.00410.0218-0.00680.0066-12.70615.975-9.6
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 120
2X-RAY DIFFRACTION2A121 - 228
3X-RAY DIFFRACTION3A229 - 500

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