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- PDB-2uw9: STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH 4-(4-chloro-phenyl)-4... -

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Basic information

Entry
Database: PDB / ID: 2uw9
TitleSTRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH 4-(4-chloro-phenyl)-4-(4-(1H-pyrazol-4-yl)-phenyl)-piperidine
Components
  • GLYCOGEN SYNTHASE KINASE-3 BETA
  • RAC-BETA SERINE/THREONINE-PROTEIN KINASE
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX / WNT SIGNALING PATHWAY / SERINE/THREONINE-PROTEIN KINASE / KINASE / TRANSFERASE / ATP-BINDING / PHOSPHORYLATION / NUCLEOTIDE-BINDING / ALTERNATIVE SPLICING
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 / beta-catenin destruction complex disassembly / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / neuron projection organization / negative regulation of type B pancreatic cell development / superior temporal gyrus development / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / positive regulation of protein localization to centrosome / maintenance of cell polarity / positive regulation of fatty acid beta-oxidation / mammary gland epithelial cell differentiation / positive regulation of cilium assembly / 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 / positive regulation of glucose metabolic process / beta-catenin destruction complex / tau-protein kinase / RAB GEFs exchange GTP for GDP on RABs / CRMPs in Sema3A signaling / heart valve development / regulation of microtubule-based process / regulation of protein export from nucleus / 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 / peripheral nervous system myelin maintenance / glycogen biosynthetic process / Maturation of nucleoprotein / cellular response to interleukin-3 / negative regulation of TOR signaling / Wnt signalosome / positive regulation of cell motility / negative regulation of protein localization to nucleus / 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 epithelial to mesenchymal transition / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / regulation of axon extension / Regulation of TP53 Activity through Association with Co-factors / G protein-coupled dopamine receptor signaling pathway / CTLA4 inhibitory signaling / regulation of axonogenesis / regulation of dendrite morphogenesis / tau-protein kinase activity / establishment of cell polarity / glycogen metabolic process / ER overload response / regulation of neuron projection development / fat cell differentiation / Regulation of MITF-M-dependent genes involved in pigmentation / protein kinase A catalytic subunit binding / Constitutive Signaling by AKT1 E17K in Cancer / CD28 dependent PI3K/Akt signaling / dynactin binding / Regulation of localization of FOXO transcription factors / NF-kappaB binding / epithelial to mesenchymal transition / positive regulation of glycogen biosynthetic process / positive regulation of protein targeting to membrane / Activation of BAD and translocation to mitochondria / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation of osteoblast differentiation / negative regulation of protein-containing complex assembly / canonical Wnt signaling pathway / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Transcriptional and post-translational regulation of MITF-M expression and activity / Cyclin E associated events during G1/S transition / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / 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 cellular response to heat / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / Regulation of TP53 Activity through Acetylation
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 ...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-GVP / RAC-beta serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsDavies, T.G. / Saxty, G. / Woodhead, S.J. / Berdini, V. / Verdonk, M.L. / Wyatt, P.G. / Boyle, R.G. / Barford, D. / Downham, R. / Garrett, M.D. / Carr, R.A.
CitationJournal: J.Med.Chem. / Year: 2007
Title: Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery.
Authors: Saxty, G. / Woodhead, S.J. / Berdini, V. / Davies, T.G. / Verdonk, M.L. / Wyatt, P.G. / Boyle, R.G. / Barford, D. / Downham, R. / Garrett, M.D. / Carr, R.A.
History
DepositionMar 19, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 8, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RAC-BETA SERINE/THREONINE-PROTEIN KINASE
C: GLYCOGEN SYNTHASE KINASE-3 BETA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3213
Polymers40,9842
Non-polymers3381
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint-5.4 kcal/mol
Surface area18560 Å2
MethodPQS
Unit cell
Length a, b, c (Å)45.058, 61.046, 132.737
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein RAC-BETA SERINE/THREONINE-PROTEIN KINASE / PROTEIN KINASE B-BETA / RAC-PK-BETA / PROTEIN KINASE AKT-2 / PROTEIN KINASE B / BETA / PKB BETA


Mass: 39860.383 Da / Num. of mol.: 1 / Fragment: KINASE CATALYTIC DOMAIN, RESIDUES 146-467
Source method: isolated from a genetically manipulated source
Details: PIFTIDE SEQUENCE (EEQEMFEDFDYIADW) REPLACES NATURAL PKB SEQUENCE AFTER RESIDUE 464C
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P31751, non-specific serine/threonine protein kinase
#2: Protein/peptide GLYCOGEN SYNTHASE KINASE-3 BETA / GSK3-BETA PEPTIDE / GSK-3 BETA


Mass: 1123.220 Da / Num. of mol.: 1 / Fragment: RESIDUES 3-12 / Source method: obtained synthetically / Details: PEPTIDE DERIVED FROM THE KINASE GSK3-BETA / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P49841, tau-protein kinase
#3: Chemical ChemComp-GVP / 4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE


Mass: 337.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20ClN3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsCLONE DOES NOT CONTAIN THE FIRST 145 RESIDUES OF THE P31751 SEQUENCE (PH-DOMAIN). RESIDUES GAMDP AT ...CLONE DOES NOT CONTAIN THE FIRST 145 RESIDUES OF THE P31751 SEQUENCE (PH-DOMAIN). RESIDUES GAMDP AT THE START OF THE CLONED SEQUENCE ARE ARTEFACTS FROM A PURIFICATION TAG, HOWEVER THESE ARE NOT VISIBLE IN THE STRUCTURE AND WERE NOT BUILT. THE CLONE CONTAINS THE SEQUENCE EEQEMFEDFDYIADW (PIFTIDE) INSTEAD OF THE P31751 SEQUENCE FROM POSITION 465 ONWARDS. RESIDUES 450 - 466 ARE DISORDERED AND HAVE NOT BEEN BUILT IN THE STRUCTURE. RESIDUES 3-12 ONLY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.51 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→44.9 Å / Num. obs: 20582 / % possible obs: 98 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.15 / Net I/σ(I): 4.6
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.5 / % possible all: 96.7

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Processing

SoftwareName: REFMAC / Version: 5.2.0019G / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→44.93 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.873 / SU B: 9.314 / SU ML: 0.231 / Cross valid method: THROUGHOUT / ESU R: 0.268 / ESU R Free: 0.245 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.305 1092 5 %RANDOM
Rwork0.222 ---
obs0.226 20582 98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 25.77 Å2
Baniso -1Baniso -2Baniso -3
1--1.04 Å20 Å20 Å2
2---0.56 Å20 Å2
3---1.61 Å2
Refinement stepCycle: LAST / Resolution: 2.1→44.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2684 0 24 162 2870
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222772
X-RAY DIFFRACTIONr_bond_other_d0.0010.021942
X-RAY DIFFRACTIONr_angle_refined_deg1.4621.9633739
X-RAY DIFFRACTIONr_angle_other_deg0.9182.9844686
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5325324
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.84323.381139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.82415497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3131522
X-RAY DIFFRACTIONr_chiral_restr0.080.2392
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023046
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02613
X-RAY DIFFRACTIONr_nbd_refined0.2080.2589
X-RAY DIFFRACTIONr_nbd_other0.1980.22001
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21331
X-RAY DIFFRACTIONr_nbtor_other0.0860.21458
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.257
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2450.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2850.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0760.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.10751625
X-RAY DIFFRACTIONr_mcbond_other0.0555660
X-RAY DIFFRACTIONr_mcangle_it0.13462620
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.13561147
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.1577.51119
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.438 79 -
Rwork0.321 1459 -
obs--95.71 %

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