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- PDB-3e88: Crystal structures of the kinase domain of AKT2 in complex with A... -

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Basic information

Entry
Database: PDB / ID: 3.0E+88
TitleCrystal structures of the kinase domain of AKT2 in complex with ATP-competitive inhibitors
Components
  • Glycogen synthase kinase-3 beta peptide
  • RAC-beta serine/threonine-protein kinase
KeywordsTRANSFERASE / AKT2 / kinase / GSK3 beta / ATP-binding / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Wnt signaling pathway
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 / AKT-mediated inactivation of FOXO1A / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / Activation of AKT2 / AKT phosphorylates targets in the nucleus / regulation of microtubule anchoring at centrosome ...retinal rod cell apoptotic process / PDE3B signalling / cellular response to high light intensity / Inhibition of TSC complex formation by PKB / AKT-mediated inactivation of FOXO1A / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / Activation of AKT2 / AKT phosphorylates targets in the nucleus / regulation of microtubule anchoring at centrosome / negative regulation of glycogen (starch) synthase activity / neuron projection organization / negative regulation of mesenchymal stem cell differentiation / beta-catenin destruction complex disassembly / negative regulation of type B pancreatic cell development / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / RUNX2 regulates genes involved in cell migration / : / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of protein localization to centrosome / : / positive regulation of fatty acid beta-oxidation / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of cilium assembly / mammary gland epithelial cell differentiation / negative regulation of protein acetylation / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / beta-catenin destruction complex / tau-protein kinase / CRMPs in Sema3A signaling / heart valve development / regulation of microtubule-based process / regulation of protein export from nucleus / peripheral nervous system myelin maintenance / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / Maturation of nucleoprotein / cellular response to interleukin-3 / Wnt signalosome / negative regulation of protein localization to nucleus / positive regulation of cell motility / glycogen biosynthetic process / negative regulation of TOR signaling / regulation of long-term synaptic potentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Maturation of nucleoprotein / AKT phosphorylates targets in the cytosol / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / G protein-coupled dopamine receptor signaling pathway / Regulation of TP53 Activity through Association with Co-factors / negative regulation of phosphoprotein phosphatase activity / regulation of dendrite morphogenesis / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / CTLA4 inhibitory signaling / glycogen metabolic process / ER overload response / fat cell differentiation / Constitutive Signaling by AKT1 E17K in Cancer / protein kinase A catalytic subunit binding / dynactin binding / CD28 dependent PI3K/Akt signaling / Regulation of localization of FOXO transcription factors / NF-kappaB binding / positive regulation of glycogen biosynthetic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Regulation of HSF1-mediated heat shock response / Activation of BAD and translocation to mitochondria / positive regulation of protein targeting to membrane / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / canonical Wnt signaling pathway / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / Cyclin E associated events during G1/S transition / regulation of cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Cyclin A:Cdk2-associated events at S phase entry / extrinsic apoptotic signaling pathway in absence of ligand / regulation of cell migration / Regulation of TP53 Activity through Acetylation / presynaptic modulation of chemical synaptic transmission
Similarity search - Function
Protein Kinase B beta, catalytic domain / Protein Kinase B, pleckstrin homology domain / Glycogen synthase kinase 3, catalytic 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. ...Protein Kinase B beta, catalytic domain / Protein Kinase B, pleckstrin homology domain / Glycogen synthase kinase 3, catalytic 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-G96 / RAC-beta serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsConcha, N.O. / Elkins, P.A. / Smallwood, A. / Ward, P.
Citation
#1: Journal: To be Published
Title: Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors
Authors: Seefeld, M.A. / Rouse, M.B. / McNulty, K.C. / Sun, L. / Wang, J. / Yamashita, D.S. / Choudhry, A. / Schaber, M.D. / Kumar, R. / Kahana, J. / Zhang, S.Y. / Minthorn, E.A. / Koretke, K.K. / ...Authors: Seefeld, M.A. / Rouse, M.B. / McNulty, K.C. / Sun, L. / Wang, J. / Yamashita, D.S. / Choudhry, A. / Schaber, M.D. / Kumar, R. / Kahana, J. / Zhang, S.Y. / Minthorn, E.A. / Koretke, K.K. / Concha, N.O. / Heerding, D.A.
History
DepositionAug 19, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: RAC-beta serine/threonine-protein kinase
B: RAC-beta serine/threonine-protein kinase
C: Glycogen synthase kinase-3 beta peptide
D: Glycogen synthase kinase-3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,3146
Polymers80,3914
Non-polymers9232
Water1,11762
1
A: RAC-beta serine/threonine-protein kinase
C: Glycogen synthase kinase-3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6573
Polymers40,1962
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2410 Å2
ΔGint-3 kcal/mol
Surface area15630 Å2
MethodPISA
2
B: RAC-beta serine/threonine-protein kinase
D: Glycogen synthase kinase-3 beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6573
Polymers40,1962
Non-polymers4621
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2420 Å2
ΔGint-5 kcal/mol
Surface area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.885, 116.885, 45.115
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number145
Space group name H-MP32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A146 - 480
2112B146 - 480
1124C3 - 12
2124D3 - 12

NCS ensembles :
ID
1
2

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Components

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


Mass: 39072.512 Da / Num. of mol.: 2 / Fragment: Akt2 kinase domain (146-480) / Mutation: S474D
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: Protein/peptide Glycogen synthase kinase-3 beta peptide / GSK-3 beta


Mass: 1123.220 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: The peptide was chemically synthesized. It is found naturally in human.
References: UniProt: P49841
#3: Chemical ChemComp-G96 / 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-6-{[(2R)-2-amino-3-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol


Mass: 461.516 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27N7O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 62 / 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: 2.21 Å3/Da / Density % sol: 44.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8
Details: 14% PEG 2KMME, 100 mM Tris pH 8.0 and 10% ethanol diffused in. Seeded., vapor diffusion, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 1, 2005 / Details: un-focused beam
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→41.21 Å / Num. obs: 23801 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 5.7 % / Rmerge(I) obs: 0.179 / Net I/σ(I): 4.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.5-2.595.70.671100
2.59-2.695.60.6371100
2.69-2.825.80.4441100
2.82-2.965.80.3331100
2.96-3.155.80.2641100
3.15-3.395.80.2011100
3.39-3.735.70.1981100
3.73-4.275.70.1351100
4.27-5.385.80.0941100
5.38-505.70.1261100

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.006data extraction
JDirectordata collection
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→41.21 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.887 / Occupancy max: 1 / Occupancy min: 1 / SU B: 24.405 / SU ML: 0.257 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 2.378 / ESU R Free: 0.345 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.273 1219 5.1 %RANDOM
Rwork0.22976 ---
obs0.23203 22560 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.795 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20.02 Å20 Å2
2--0.04 Å20 Å2
3----0.06 Å2
Refinement stepCycle: LAST / Resolution: 2.5→41.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5426 0 68 62 5556
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0225622
X-RAY DIFFRACTIONr_bond_other_d0.0010.023934
X-RAY DIFFRACTIONr_angle_refined_deg1.171.9847588
X-RAY DIFFRACTIONr_angle_other_deg0.76439488
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1815656
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.95222.993274
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.59115990
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.1511548
X-RAY DIFFRACTIONr_chiral_restr0.0520.2806
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026136
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021236
X-RAY DIFFRACTIONr_nbd_refined0.180.21140
X-RAY DIFFRACTIONr_nbd_other0.1720.23995
X-RAY DIFFRACTIONr_nbtor_refined0.1760.22702
X-RAY DIFFRACTIONr_nbtor_other0.0790.22836
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1130.2140
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.120.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2040.283
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0430.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5211.54291
X-RAY DIFFRACTIONr_mcbond_other0.0731.51336
X-RAY DIFFRACTIONr_mcangle_it0.55525312
X-RAY DIFFRACTIONr_scbond_it0.39132905
X-RAY DIFFRACTIONr_scangle_it0.6014.52276
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A1893tight positional0.010.05
1A2630medium positional0.170.5
2C141medium positional0.260.5
1A1893tight thermal0.010.5
1A2630medium thermal0.062
2C141medium thermal0.062
LS refinement shellResolution: 2.501→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 100 -
Rwork0.353 1615 -
obs--99.31 %
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)
11.003-0.62020.1480.88190.13830.85690.0298-0.0285-0.0392-0.0389-0.03110.0456-0.0648-0.06150.00130.00540.01-0.0102-0.0311-0.0212-0.0029-15.75748.383-3.766
20.3970.25210.17081.3131-0.06370.8072-0.043-0.0150.037-0.01820.03710.0634-0.08120.00560.006-0.0031-0.0235-0.0165-0.0114-0.0023-0.0101-24.4194.0923.744
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA146 - 4801 - 335
2X-RAY DIFFRACTION1CC3 - 121 - 10
3X-RAY DIFFRACTION2BB146 - 4801 - 335
4X-RAY DIFFRACTION2DD3 - 121 - 10

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