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- PDB-3mv5: Crystal structure of Akt-1-inhibitor complexes -

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Basic information

Entry
Database: PDB / ID: 3mv5
TitleCrystal structure of Akt-1-inhibitor complexes
Components
  • GSK3-beta peptide
  • v-akt murine thymoma viral oncogene homolog 1 (AKT1)
KeywordsTRANSFERASE / kinase inhibitor
Function / homology
Function and homology information


glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development ...glycogen cell differentiation involved in embryonic placenta development / regulation of tRNA methylation / response to insulin-like growth factor stimulus / potassium channel activator activity / negative regulation of protein localization to lysosome / positive regulation of protein localization to endoplasmic reticulum / maintenance of protein location in mitochondrion / negative regulation of lymphocyte migration / cellular response to decreased oxygen levels / regulation of type B pancreatic cell development / AKT-mediated inactivation of FOXO1A / maternal placenta development / Negative regulation of the PI3K/AKT network / negative regulation of long-chain fatty acid import across plasma membrane / establishment of protein localization to mitochondrion / negative regulation of fatty acid beta-oxidation / AKT phosphorylates targets in the nucleus / regulation of glycogen biosynthetic process / cellular response to oxidised low-density lipoprotein particle stimulus / 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 / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / superior temporal gyrus development / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / negative regulation of dopaminergic neuron differentiation / positive regulation of organ growth / maintenance of cell polarity / positive regulation of protein localization to centrosome / : / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / MTOR signalling / fibroblast migration / interleukin-18-mediated signaling pathway / positive regulation of sodium ion transport / positive regulation of cilium assembly / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein acetylation / negative regulation of protein serine/threonine kinase activity / 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 / positive regulation of endodeoxyribonuclease activity / tau-protein kinase / positive regulation of protein localization to cell surface / CRMPs in Sema3A signaling / heart valve development / regulation of microtubule-based process / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / protein serine/threonine kinase inhibitor activity / regulation of protein export from nucleus / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / 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 / sphingosine-1-phosphate receptor signaling pathway / positive regulation of fibroblast migration / cellular response to interleukin-3 / cell migration involved in sprouting angiogenesis / response to growth hormone / Wnt signalosome / negative regulation of protein localization to nucleus / anoikis / 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 / labyrinthine layer blood vessel development / execution phase of apoptosis / response to food / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of cell-matrix adhesion / response to UV-A / regulation of myelination / regulation of postsynapse organization / regulation of axon extension / regulation of neuron projection development / G protein-coupled dopamine receptor signaling pathway / KSRP (KHSRP) binds and destabilizes mRNA
Similarity search - Function
Protein kinase B alpha, 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 alpha, 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-XFE / RAC-alpha serine/threonine-protein kinase / RAC-alpha serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.47 Å
AuthorsPandit, J.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Design of selective, ATP-competitive inhibitors of Akt.
Authors: Freeman-Cook, K.D. / Autry, C. / Borzillo, G. / Gordon, D. / Barbacci-Tobin, E. / Bernardo, V. / Briere, D. / Clark, T. / Corbett, M. / Jakubczak, J. / Kakar, S. / Knauth, E. / Lippa, B. / ...Authors: Freeman-Cook, K.D. / Autry, C. / Borzillo, G. / Gordon, D. / Barbacci-Tobin, E. / Bernardo, V. / Briere, D. / Clark, T. / Corbett, M. / Jakubczak, J. / Kakar, S. / Knauth, E. / Lippa, B. / Luzzio, M.J. / Mansour, M. / Martinelli, G. / Marx, M. / Nelson, K. / Pandit, J. / Rajamohan, F. / Robinson, S. / Subramanyam, C. / Wei, L. / Wythes, M. / Morris, J.
History
DepositionMay 3, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 6, 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_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_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: v-akt murine thymoma viral oncogene homolog 1 (AKT1)
C: GSK3-beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,0044
Polymers40,7312
Non-polymers2722
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1450 Å2
ΔGint-6 kcal/mol
Surface area15080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.706, 55.417, 93.287
Angle α, β, γ (deg.)90.000, 104.000, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein v-akt murine thymoma viral oncogene homolog 1 (AKT1)


Mass: 39608.094 Da / Num. of mol.: 1 / Fragment: Kinase Domain / Mutation: S473D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT-1, AKT1 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: B2RAM5, UniProt: P31749*PLUS, non-specific serine/threonine protein kinase
#2: Protein/peptide GSK3-beta peptide


Mass: 1123.220 Da / Num. of mol.: 1 / Fragment: 10 residue peptide from GSK3-b (Residues 3-12) / Source method: obtained synthetically / References: UniProt: P49841*PLUS
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-XFE / (3R)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine


Mass: 217.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.63 Å3/Da / Density % sol: 53.23 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ DW / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Details: Vari-max optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.47→90.54 Å / Num. obs: 14895 / % possible obs: 97 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.13 % / Rmerge(I) obs: 0.082 / Χ2: 0.99 / Net I/σ(I): 10.5 / Scaling rejects: 353
Reflection shellResolution: 2.47→2.56 Å / Redundancy: 2.68 % / Rmerge(I) obs: 0.331 / Mean I/σ(I) obs: 3.1 / Num. measured all: 2986 / Num. unique all: 1104 / Χ2: 1.19 / % possible all: 72.7

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Processing

Software
NameVersionClassificationNB
d*TREK8.0SSIdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
d*TREKdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.47→19.92 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.879 / WRfactor Rfree: 0.246 / WRfactor Rwork: 0.18 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.804 / SU B: 10.355 / SU ML: 0.233 / SU R Cruickshank DPI: 0.478 / SU Rfree: 0.316 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.316 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.282 758 5.1 %RANDOM
Rwork0.2 ---
obs0.205 14880 96.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 66.94 Å2 / Biso mean: 32.119 Å2 / Biso min: 4.59 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å2-0.51 Å2
2---0.03 Å20 Å2
3---1 Å2
Refinement stepCycle: LAST / Resolution: 2.47→19.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2670 0 17 56 2743
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0222758
X-RAY DIFFRACTIONr_angle_refined_deg2.1861.9753714
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7495325
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.823.333135
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.72615496
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7391520
X-RAY DIFFRACTIONr_chiral_restr0.1360.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022091
X-RAY DIFFRACTIONr_nbd_refined0.2350.21214
X-RAY DIFFRACTIONr_nbtor_refined0.3180.21833
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1470.2108
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.130.223
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1540.25
X-RAY DIFFRACTIONr_mcbond_it1.0731.51676
X-RAY DIFFRACTIONr_mcangle_it1.82522613
X-RAY DIFFRACTIONr_scbond_it2.831252
X-RAY DIFFRACTIONr_scangle_it4.1224.51101
LS refinement shellResolution: 2.47→2.536 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.508 25 -
Rwork0.265 713 -
all-738 -
obs--64.06 %

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