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- PDB-3d0e: Crystal structure of human Akt2 in complex with GSK690693 -

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Basic information

Entry
Database: PDB / ID: 3d0e
TitleCrystal structure of human Akt2 in complex with GSK690693
ComponentsRAC-beta serine/threonine-protein kinase
KeywordsTRANSFERASE INHIBITOR / human / AKT2 / inhibitor / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Transferase
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 / Regulation of TP53 Activity through Acetylation / FLT3 Signaling / Downregulation of ERBB2:ERBB3 signaling / 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 / 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 / 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 / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-G93 / RAC-beta serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsConcha, N.O. / Smallwood, A.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.
Authors: Heerding, D.A. / Rhodes, N. / Leber, J.D. / Clark, T.J. / Keenan, R.M. / Lafrance, L.V. / Li, M. / Safonov, I.G. / Takata, D.T. / Venslavsky, J.W. / Yamashita, D.S. / Choudhry, A.E. / ...Authors: Heerding, D.A. / Rhodes, N. / Leber, J.D. / Clark, T.J. / Keenan, R.M. / Lafrance, L.V. / Li, M. / Safonov, I.G. / Takata, D.T. / Venslavsky, J.W. / Yamashita, D.S. / Choudhry, A.E. / Copeland, R.A. / Lai, Z. / Schaber, M.D. / Tummino, P.J. / Strum, S.L. / Wood, E.R. / Duckett, D.R. / Eberwein, D. / Knick, V.B. / Lansing, T.J. / McConnell, R.T. / Zhang, S. / Minthorn, E.A. / Concha, N.O. / Warren, G.L. / Kumar, R.
History
DepositionMay 1, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Dec 28, 2016Group: Non-polymer description
Revision 1.3Oct 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 1.4Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,9964
Polymers78,1452
Non-polymers8512
Water8,107450
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: RAC-beta serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4982
Polymers39,0731
Non-polymers4251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: RAC-beta serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,4982
Polymers39,0731
Non-polymers4251
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)116.489, 116.489, 45.119
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: LYS / Beg label comp-ID: LYS / End auth comp-ID: ARG / End label comp-ID: ARG / Refine code: 5 / Auth seq-ID: 146 - 480 / Label seq-ID: 1 - 335

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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: kinase domain / Mutation: S474D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT2 / Cell line (production host): SF9 / Production host: spodoptera frugiperda (fall armyworm)
References: UniProt: P31751, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-G93 / 4-{2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3S)-piperidin-3-ylmethoxy]-1H-imidazo[4,5-c]pyridin-4-yl}-2-methylbut-3 -yn-2-ol / GSK690693


Mass: 425.484 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 450 / Source method: isolated from a natural source / Formula: H2O
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: 2.26 Å3/Da / Density % sol: 45.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8
Details: 14% PEG 4K, 10% isopropanol, pH 8.0, 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: Quantum 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→35.67 Å / Num. obs: 46301 / % possible obs: 99.9 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.102 / Χ2: 1.33 / Net I/σ(I): 7.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2-2.074.10.61546821.211199.9
2.07-2.154.10.48246501.207199.9
2.15-2.254.10.32345761.395199.9
2.25-2.374.20.29146521.2051100
2.37-2.524.20.19745971.1171100
2.52-2.714.20.1546341.0941100
2.71-2.994.20.09946431.0931100
2.99-3.424.20.07146321.331100
3.42-4.314.20.05646211.779199.8
4.31-504.20.04546141.879199.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.005data extraction
RefinementResolution: 2→35.67 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.918 / SU B: 9.744 / SU ML: 0.144 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.223 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.246 2346 5.1 %RANDOM
Rwork0.206 ---
obs0.208 46277 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: 19.342 Å2
Baniso -1Baniso -2Baniso -3
1-0.46 Å20.23 Å20 Å2
2--0.46 Å20 Å2
3----0.69 Å2
Refinement stepCycle: LAST / Resolution: 2→35.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5314 0 62 450 5826
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0225506
X-RAY DIFFRACTIONr_bond_other_d0.0010.023848
X-RAY DIFFRACTIONr_angle_refined_deg1.2691.9867440
X-RAY DIFFRACTIONr_angle_other_deg0.81139300
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5665644
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.16123.209268
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.92215968
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9831544
X-RAY DIFFRACTIONr_chiral_restr0.060.2790
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.026016
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021186
X-RAY DIFFRACTIONr_nbd_refined0.1810.21126
X-RAY DIFFRACTIONr_nbd_other0.1790.24009
X-RAY DIFFRACTIONr_nbtor_refined0.1740.22625
X-RAY DIFFRACTIONr_nbtor_other0.0790.22745
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2389
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1480.226
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2670.2114
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1250.236
X-RAY DIFFRACTIONr_mcbond_it0.5691.54223
X-RAY DIFFRACTIONr_mcbond_other0.0661.51306
X-RAY DIFFRACTIONr_mcangle_it0.60925216
X-RAY DIFFRACTIONr_scbond_it0.8532732
X-RAY DIFFRACTIONr_scangle_it1.2284.52224
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
1909MEDIUM POSITIONAL0.040.5
2655LOOSE POSITIONAL0.275
1909MEDIUM THERMAL0.122
2655LOOSE THERMAL0.2510
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.362 173 -
Rwork0.301 3331 -
all-3504 -
obs--99.89 %
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)
10.96580.5551-0.06870.7675-0.26190.97980.0748-0.0053-0.00270.0319-0.0732-0.0636-0.11210.0339-0.0016-0.0276-0.01870.0079-0.07450.0053-0.050415.6613-18.60163.7316
20.3183-0.20330.19791.5257-0.26580.9553-0.03890.03660.04290.07460.0372-0.0337-0.0746-0.07250.0017-0.05110.03120.0011-0.0550.01-0.054823.9523-63.0005-3.7824
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA146 - 4801 - 335
2X-RAY DIFFRACTION2BB146 - 4801 - 335

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