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- PDB-3o96: Crystal Structure of Human AKT1 with an Allosteric Inhibitor -

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Basic information

Entry
Database: PDB / ID: 3o96
TitleCrystal Structure of Human AKT1 with an Allosteric Inhibitor
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Pleckstrin homology / protein kinase / allosteric 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 / negative regulation of cilium assembly / positive regulation of I-kappaB phosphorylation / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / response to fluid shear stress / RUNX2 regulates genes involved in cell migration / positive regulation of organ growth / MTOR signalling / fibroblast migration / interleukin-18-mediated signaling pathway / positive regulation of sodium ion transport / mammary gland epithelial cell differentiation / negative regulation of endopeptidase activity / negative regulation of protein serine/threonine kinase activity / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / positive regulation of endodeoxyribonuclease activity / response to growth factor / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of protein localization to cell surface / protein serine/threonine kinase inhibitor activity / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / sphingosine-1-phosphate receptor signaling pathway / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / response to growth hormone / anoikis / glycogen biosynthetic process / AKT phosphorylates targets in the cytosol / labyrinthine layer blood vessel development / execution phase of apoptosis / response to food / response to UV-A / regulation of myelination / regulation of postsynapse organization / regulation of neuron projection development / KSRP (KHSRP) binds and destabilizes mRNA / Regulation of TP53 Activity through Association with Co-factors / mammalian oogenesis stage / negative regulation of macroautophagy / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / activation-induced cell death of T cells / negative regulation of Notch signaling pathway / behavioral response to pain / non-canonical NF-kappaB signal transduction / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / apoptotic mitochondrial changes / CD28 dependent PI3K/Akt signaling / phosphatidylinositol-3,4,5-trisphosphate binding / Regulation of localization of FOXO transcription factors / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of glycogen biosynthetic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / TOR signaling / Activation of BAD and translocation to mitochondria / positive regulation of blood vessel endothelial cell migration / cellular response to vascular endothelial growth factor stimulus / positive regulation of fat cell differentiation / canonical NF-kappaB signal transduction / positive regulation of G1/S transition of mitotic cell cycle / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / positive regulation of lipid biosynthetic process / Cyclin E associated events during G1/S transition / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Cyclin A:Cdk2-associated events at S phase entry / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / lipopolysaccharide-mediated signaling pathway / regulation of cell migration / negative regulation of protein ubiquitination / cellular response to epidermal growth factor stimulus / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / positive regulation of endothelial cell proliferation / striated muscle cell differentiation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
Similarity search - Function
Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain ...Protein kinase B alpha, catalytic domain / Protein Kinase B, pleckstrin homology domain / Protein kinase, C-terminal / Protein kinase C terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / 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 / Roll / 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 Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-IQO / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsVoegtli, W.C. / Wu, W.-I. / Lord-Ondash, H.A. / Dizon, F.P. / Vigers, G.P.A. / Brandhuber, B.J.
CitationJournal: Plos One / Year: 2010
Title: Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition.
Authors: Wu, W.I. / Voegtli, W.C. / Sturgis, H.L. / Dizon, F.P. / Vigers, G.P. / Brandhuber, B.J.
History
DepositionAug 3, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 13, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_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

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Assembly

Deposited unit
A: RAC-alpha serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,4152
Polymers51,8631
Non-polymers5521
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.310, 69.940, 61.850
Angle α, β, γ (deg.)90.00, 100.60, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein RAC-alpha serine/threonine-protein kinase / RAC-PK-alpha / Protein kinase B / PKB / Proto-oncogene c-Akt


Mass: 51863.094 Da / Num. of mol.: 1 / Fragment: unp residues 2-443
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Cell line (production host): HI5 INSECT CELLS / Production host: TRICHOPLUSIA NI (cabbage looper)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-IQO / 1-(1-(4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)benzyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one / 1-{1-[4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


Mass: 551.640 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H29N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.02 Å3/Da / Density % sol: 39.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 50 mM acetate-citrate buffer, 21% PEG MME 2000, pH 5.2, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 22, 2009
RadiationMonochromator: Osmic confocal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.7→25 Å / Num. all: 11474 / Num. obs: 11462 / % possible obs: 99.9 % / Redundancy: 3.5 % / Biso Wilson estimate: 68.3 Å2 / Rmerge(I) obs: 0.078 / Net I/σ(I): 8.1
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.382 / Mean I/σ(I) obs: 2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
CNX2005refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY CODES 1MRV and 1UNP

1mrv

1unp


Resolution: 2.7→24.7 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 1532264.03 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.308 643 5.6 %RANDOM
Rwork0.245 ---
all0.249 11459 --
obs0.249 11459 99.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.4784 Å2 / ksol: 0.336736 e/Å3
Displacement parametersBiso mean: 52.4 Å2
Baniso -1Baniso -2Baniso -3
1--4.09 Å20 Å23.5 Å2
2--1 Å20 Å2
3---3.08 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.52 Å0.38 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.23 Å
Refinement stepCycle: LAST / Resolution: 2.7→24.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3031 0 42 21 3094
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d22
X-RAY DIFFRACTIONc_improper_angle_d0.55
X-RAY DIFFRACTIONc_mcbond_it1.481.5
X-RAY DIFFRACTIONc_mcangle_it2.572
X-RAY DIFFRACTIONc_scbond_it1.692
X-RAY DIFFRACTIONc_scangle_it2.642.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.7→2.87 Å / Rfactor Rfree error: 0.037 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.384 108 5.7 %
Rwork0.317 1787 -
obs-935 99.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paprotein.top
X-RAY DIFFRACTION2inh_viii.parinh_viii.top
X-RAY DIFFRACTION3water_rep.parawater.top

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