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- PDB-6hhf: Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT... -

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Basic information

Entry
Database: PDB / ID: 6hhf
TitleCrystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor Borussertib
ComponentsRAC-alpha serine/threonine-protein kinase
KeywordsTRANSFERASE / Akt1 / borussertib / covalent-allosteric
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 / regulation of glycogen biosynthetic process / AKT phosphorylates targets in the nucleus / 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 / mammalian oogenesis stage / RAB GEFs exchange GTP for GDP on RABs / positive regulation of glucose metabolic process / positive regulation of endodeoxyribonuclease activity / positive regulation of protein localization to cell surface / protein serine/threonine kinase inhibitor activity / cellular response to granulocyte macrophage colony-stimulating factor stimulus / response to growth factor / activation-induced cell death of T cells / negative regulation of leukocyte cell-cell adhesion / phosphatidylinositol-3,4-bisphosphate binding / peripheral nervous system myelin maintenance / sphingosine-1-phosphate receptor signaling pathway / glycogen biosynthetic process / positive regulation of fibroblast migration / cell migration involved in sprouting angiogenesis / anoikis / response to growth hormone / AKT phosphorylates targets in the cytosol / execution phase of apoptosis / labyrinthine layer blood vessel development / 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 / negative regulation of macroautophagy / CTLA4 inhibitory signaling / negative regulation of cGAS/STING signaling pathway / negative regulation of Notch signaling pathway / behavioral response to pain / negative regulation of release of cytochrome c from mitochondria / Constitutive Signaling by AKT1 E17K in Cancer / non-canonical NF-kappaB signal transduction / apoptotic mitochondrial changes / CD28 dependent PI3K/Akt signaling / phosphatidylinositol-3,4,5-trisphosphate binding / carbohydrate transport / Regulation of localization of FOXO transcription factors / positive regulation of cyclin-dependent protein serine/threonine kinase activity / TOR signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of glycogen biosynthetic process / Activation of BAD and translocation to mitochondria / positive regulation of fat cell differentiation / positive regulation of blood vessel endothelial cell migration / canonical NF-kappaB signal transduction / cellular response to vascular endothelial growth factor stimulus / positive regulation of G1/S transition of mitotic cell cycle / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / eNOS activation / Cyclin E associated events during G1/S transition / positive regulation of lipid biosynthetic process / 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 endothelial cell proliferation / positive regulation of TORC1 signaling / 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
Borussertib / RAC-alpha serine/threonine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsLandel, I. / Weisner, J. / Mueller, M.P. / Scheinpflug, R. / Rauh, D.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and Research01ZX1303C Germany
CitationJournal: Cancer Res. / Year: 2019
Title: Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib inKRAS-Mutant Pancreatic and Colorectal Cancer.
Authors: Weisner, J. / Landel, I. / Reintjes, C. / Uhlenbrock, N. / Trajkovic-Arsic, M. / Dienstbier, N. / Hardick, J. / Ladigan, S. / Lindemann, M. / Smith, S. / Quambusch, L. / Scheinpflug, R. / ...Authors: Weisner, J. / Landel, I. / Reintjes, C. / Uhlenbrock, N. / Trajkovic-Arsic, M. / Dienstbier, N. / Hardick, J. / Ladigan, S. / Lindemann, M. / Smith, S. / Quambusch, L. / Scheinpflug, R. / Depta, L. / Gontla, R. / Unger, A. / Muller, H. / Baumann, M. / Schultz-Fademrecht, C. / Gunther, G. / Maghnouj, A. / Muller, M.P. / Pohl, M. / Teschendorf, C. / Wolters, H. / Viebahn, R. / Tannapfel, A. / Uhl, W. / Hengstler, J.G. / Hahn, S.A. / Siveke, J.T. / Rauh, D.
History
DepositionAug 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2019Provider: repository / Type: Initial release
Revision 1.1May 15, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc / pdbx_struct_ref_seq_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _pdbx_struct_ref_seq_depositor_info.db_seq_one_letter_code
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)52,3452
Polymers51,7461
Non-polymers5991
Water543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area18280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.370, 68.440, 102.510
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-alpha serine/threonine-protein kinase / Protein kinase B / PKB / Protein kinase B alpha / PKB alpha / Proto-oncogene c-Akt / RAC-PK-alpha


Mass: 51746.035 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKT1, PKB, RAC / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P31749, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-G4K / Borussertib


Mass: 598.694 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H34N6O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.18 Å3/Da / Density % sol: 43.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 1.25 mM Na-acetate, 3.75 mM Na-citrate, 15% v/v PEG 2000 MME, pH 5.2, 3 mg/mL Akt1 (in 25 mM TRIS, 100 mM NaCl, 10 % Glycerol, 5 mM DTT, pH 7.5), 1 uL reservoir + 1 uL protein solution

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97862 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 26, 2016
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97862 Å / Relative weight: 1
ReflectionResolution: 2.9→46.89 Å / Num. obs: 10515 / % possible obs: 100 % / Redundancy: 12.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.081 / Rrim(I) all: 0.084 / Net I/σ(I): 18.38
Reflection shellResolution: 2.9→3 Å / Redundancy: 13.7 % / Rmerge(I) obs: 1.69 / Mean I/σ(I) obs: 1.57 / Num. unique obs: 994 / CC1/2: 0.77 / Rrim(I) all: 1.76 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6HHG

6hhg


Resolution: 2.9→46.889 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 34.48
RfactorNum. reflection% reflection
Rfree0.2736 526 5.01 %
Rwork0.2305 --
obs0.2327 10508 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.9→46.889 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3034 0 45 3 3082
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023161
X-RAY DIFFRACTIONf_angle_d0.6914260
X-RAY DIFFRACTIONf_dihedral_angle_d13.0191206
X-RAY DIFFRACTIONf_chiral_restr0.027442
X-RAY DIFFRACTIONf_plane_restr0.002534
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9003-3.19210.37211280.3312439X-RAY DIFFRACTION100
3.1921-3.65390.27691300.25642463X-RAY DIFFRACTION100
3.6539-4.60290.28841310.23362481X-RAY DIFFRACTION100
4.6029-46.89540.25481370.21162599X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 8.7546 Å / Origin y: 4.163 Å / Origin z: 11.5336 Å
111213212223313233
T0.7384 Å2-0.0009 Å20.0309 Å2-0.5978 Å20.0023 Å2--0.6048 Å2
L3.7377 °2-0.832 °20.3583 °2-2.76 °2-0.8169 °2--3.2058 °2
S0.0494 Å °0.1281 Å °-0.0848 Å °-0.3271 Å °0.0016 Å °-0.035 Å °0.0938 Å °-0.0259 Å °-0.0604 Å °
Refinement TLS groupSelection details: (chain A)

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