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

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Basic information

Entry
Database: PDB / ID: 3mvh
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


regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / response to insulin-like growth factor stimulus / negative regulation of fatty acid beta-oxidation / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / cellular response to decreased oxygen levels ...regulation of tRNA methylation / negative regulation of protein maturation / mammalian oogenesis stage / response to insulin-like growth factor stimulus / negative regulation of fatty acid beta-oxidation / regulation of glycogen biosynthetic process / positive regulation of protein localization to endoplasmic reticulum / negative regulation of lymphocyte migration / negative regulation of protein localization to lysosome / cellular response to decreased oxygen levels / cellular response to rapamycin / maintenance of protein location in mitochondrion / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / regulation of type B pancreatic cell development / maternal placenta development / establishment of protein localization to mitochondrion / activation-induced cell death of T cells / potassium channel activator activity / AKT phosphorylates targets in the nucleus / cellular response to oxidised low-density lipoprotein particle stimulus / negative regulation of cilium assembly / negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / positive regulation of glucose metabolic process / cellular response to peptide / positive regulation of TORC2 signaling / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / interleukin-18-mediated signaling pathway / mammary gland epithelial cell differentiation / fibroblast migration / positive regulation of sodium ion transport / MTOR signalling / response to fluid shear stress / response to growth factor / complement receptor mediated signaling pathway / cellular response to granulocyte macrophage colony-stimulating factor stimulus / RAB GEFs exchange GTP for GDP on RABs / negative regulation of leukocyte cell-cell adhesion / glycogen biosynthetic process / peripheral nervous system myelin maintenance / phosphatidylinositol-3,4-bisphosphate binding / positive regulation of protein localization to cell surface / sphingosine-1-phosphate receptor signaling pathway / positive regulation of endodeoxyribonuclease activity / phosphorylation / cell migration involved in sprouting angiogenesis / response to growth hormone / regulation of postsynapse organization / anoikis / AKT phosphorylates targets in the cytosol / TORC2 complex binding / positive regulation of fibroblast migration / regulation of myelination / labyrinthine layer blood vessel development / Regulation of TP53 Activity through Association with Co-factors / response to UV-A / execution phase of apoptosis / KSRP (KHSRP) binds and destabilizes mRNA / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / response to food / Co-inhibition by CTLA4 / negative regulation of macroautophagy / negative regulation of cGAS/STING signaling pathway / cellular response to stress / negative regulation of release of cytochrome c from mitochondria / regulation of neuron projection development / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of PERK-mediated unfolded protein response / apoptotic mitochondrial changes / positive regulation of protein metabolic process / phosphatidylinositol-3,4,5-trisphosphate binding / TOR signaling / behavioral response to pain / Regulation of localization of FOXO transcription factors / peptidyl-threonine phosphorylation / protein serine/threonine kinase inhibitor activity / cellular response to vascular endothelial growth factor stimulus / negative regulation of Notch signaling pathway / CD28 dependent PI3K/Akt signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of blood vessel endothelial cell migration / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / positive regulation of glycogen biosynthetic process / Mitochondrial unfolded protein response (UPRmt) / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / positive regulation of fat cell differentiation / vascular endothelial cell response to laminar fluid shear stress / positive regulation of lipid biosynthetic process / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / T cell costimulation / nitric oxide metabolic process / Regulation of TP53 Activity through Acetylation
Similarity search - Function
Protein kinase B alpha, 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 alpha, 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-WFE / RAC-alpha serine/threonine-protein kinase / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.01 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 4, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Revision 1.3Oct 6, 2021Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_conn_angle ...database_2 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_asym_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
Revision 1.4Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: v-akt murine thymoma viral oncogene homolog 1 (AKT1)
B: GSK3-beta peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1874
Polymers40,7312
Non-polymers4552
Water4,450247
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1420 Å2
ΔGint-7 kcal/mol
Surface area14780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.354, 55.261, 92.314
Angle α, β, γ (deg.)90.000, 102.640, 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: unidentified baculovirus / 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
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-WFE / N-{[(3S)-3-amino-1-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide


Mass: 400.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22F2N6O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 247 / 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: 2.59 Å3/Da / Density % sol: 52.47 %

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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 IV++ / 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: 2.01→90.17 Å / Num. obs: 27827 / % possible obs: 99.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3 % / Rmerge(I) obs: 0.085 / Χ2: 1.684 / Net I/σ(I): 26.1
Reflection shellResolution: 2.01→2.08 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.155 / Num. unique all: 2690 / Χ2: 1.569 / % possible all: 98.2

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.01→50 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.251 / WRfactor Rwork: 0.192 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.848 / SU B: 3.447 / SU ML: 0.1 / SU R Cruickshank DPI: 0.164 / SU Rfree: 0.158 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1392 5 %RANDOM
Rwork0.178 ---
obs0.181 27814 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 75.04 Å2 / Biso mean: 28.377 Å2 / Biso min: 8.74 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20.52 Å2
2--0.1 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 2.01→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2637 0 30 247 2914
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.0222785
X-RAY DIFFRACTIONr_angle_refined_deg2.1811.983760
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0855329
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.29223.529136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.66615501
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6181519
X-RAY DIFFRACTIONr_chiral_restr0.1640.2390
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022126
X-RAY DIFFRACTIONr_nbd_refined0.2350.21368
X-RAY DIFFRACTIONr_nbtor_refined0.3130.21892
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1750.2240
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1960.229
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1940.216
X-RAY DIFFRACTIONr_mcbond_it1.7271.51703
X-RAY DIFFRACTIONr_mcangle_it2.27522632
X-RAY DIFFRACTIONr_scbond_it3.70331292
X-RAY DIFFRACTIONr_scangle_it5.2164.51128
LS refinement shellResolution: 2.01→2.06 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.277 104 -
Rwork0.178 1827 -
all-1931 -
obs--94.98 %

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