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- PDB-2xh5: Structure of 4-(4-tert-Butylbenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin... -

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Basic information

Entry
Database: PDB / ID: 2xh5
TitleStructure of 4-(4-tert-Butylbenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4- yl)piperidin-4-amine bound to PKB
Components
  • GLYCOGEN SYNTHASE KINASE-3 BETA
  • RAC-BETA SERINE/THREONINE-PROTEIN KINASE
KeywordsTRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / NUCLEOTIDE-BINDING / WNT SIGNALING PATHWAY / KINASE / PHOSPHOPROTEIN
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 / positive regulation of cap-dependent translational initiation / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / Activation of AKT2 / AKT phosphorylates targets in the nucleus ...retinal rod cell apoptotic process / PDE3B signalling / cellular response to high light intensity / Inhibition of TSC complex formation by PKB / positive regulation of cap-dependent translational initiation / AKT-mediated inactivation of FOXO1A / negative regulation of long-chain fatty acid import across plasma membrane / Negative regulation of the PI3K/AKT network / Activation of AKT2 / AKT phosphorylates targets in the nucleus / neuron projection organization / regulation of microtubule anchoring at centrosome / negative regulation of type B pancreatic cell development / negative regulation of glycogen (starch) synthase activity / negative regulation of mesenchymal stem cell differentiation / positive regulation of glucose metabolic process / superior temporal gyrus development / positive regulation of protein localization to cilium / negative regulation of glycogen biosynthetic process / positive regulation of fatty acid beta-oxidation / RUNX2 regulates genes involved in cell migration / negative regulation of TORC2 signaling / negative regulation of dopaminergic neuron differentiation / maintenance of cell polarity / positive regulation of protein localization to centrosome / mammary gland epithelial cell differentiation / positive regulation of cilium assembly / CRMPs in Sema3A signaling / heart valve development / tau-protein kinase / beta-catenin destruction complex / RAB GEFs exchange GTP for GDP on RABs / glycogen biosynthetic process / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / peripheral nervous system myelin maintenance / regulation of protein export from nucleus / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / cellular response to interleukin-3 / 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 / Wnt signalosome / regulation of long-term synaptic potentiation / negative regulation of TOR signaling / negative regulation of protein localization to nucleus / regulation of microtubule-based process / AKT phosphorylates targets in the cytosol / Disassembly of the destruction complex and recruitment of AXIN to the membrane / negative regulation of calcineurin-NFAT signaling cascade / regulation of axon extension / positive regulation of cell motility / Regulation of TP53 Activity through Association with Co-factors / Maturation of nucleoprotein / negative regulation of epithelial to mesenchymal transition / tau-protein kinase activity / positive regulation of cell-matrix adhesion / regulation of axonogenesis / G protein-coupled dopamine receptor signaling pathway / Co-inhibition by CTLA4 / glycogen metabolic process / ER overload response / regulation of dendrite morphogenesis / regulation of neuron projection development / negative regulation of PERK-mediated unfolded protein response / Constitutive Signaling by AKT1 E17K in Cancer / fat cell differentiation / protein kinase A catalytic subunit binding / establishment of cell polarity / Regulation of MITF-M-dependent genes involved in pigmentation / dynactin binding / Regulation of localization of FOXO transcription factors / epithelial to mesenchymal transition / CD28 dependent PI3K/Akt signaling / Regulation of HSF1-mediated heat shock response / Activation of BAD and translocation to mitochondria / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of protein targeting to membrane / positive regulation of glycogen biosynthetic process / canonical Wnt signaling pathway / NF-kappaB binding / negative regulation of osteoblast differentiation / positive regulation of protein binding / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Cyclin E associated events during G1/S transition / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of protein-containing complex assembly / Cyclin A:Cdk2-associated events at S phase entry / regulation of cellular response to heat / Regulation of TP53 Activity through Acetylation / extrinsic apoptotic signaling pathway / cellular response to retinoic acid / extrinsic apoptotic signaling pathway in absence of ligand / FLT3 Signaling / positive regulation of autophagy
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 / PH domain / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. ...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 / PH domain / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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-X37 / RAC-beta serine/threonine-protein kinase / Glycogen synthase kinase-3 beta
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å
AuthorsDavies, T.G. / McHardy, T. / Caldwell, J.J. / Cheung, K.M. / Hunter, L.J. / Taylor, K. / Rowlands, M. / Ruddle, R. / Henley, A. / Brandon, A.D. ...Davies, T.G. / McHardy, T. / Caldwell, J.J. / Cheung, K.M. / Hunter, L.J. / Taylor, K. / Rowlands, M. / Ruddle, R. / Henley, A. / Brandon, A.D. / Valenti, M. / Fazal, L. / Seavers, L. / Raynaud, F.I. / Eccles, S.A. / Aherne, G.W. / Garrett, M.D. / Collins, I.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Discovery of 4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides as Selective, Orally Active Inhibitors of Protein Kinase B (Akt).
Authors: Mchardy, T. / Caldwell, J.J. / Cheung, K.M. / Hunter, L.J. / Taylor, K. / Rowlands, M. / Ruddle, R. / Henley, A. / De Haven Brandon, A. / Valenti, M. / Davies, T.G. / Fazal, L. / Seavers, L. ...Authors: Mchardy, T. / Caldwell, J.J. / Cheung, K.M. / Hunter, L.J. / Taylor, K. / Rowlands, M. / Ruddle, R. / Henley, A. / De Haven Brandon, A. / Valenti, M. / Davies, T.G. / Fazal, L. / Seavers, L. / Raynaud, F.I. / Eccles, S.A. / Aherne, G.W. / Garrett, M.D. / Collins, I.
History
DepositionJun 9, 2010Deposition site: PDBE / Processing site: PDBE
SupersessionJun 16, 2010ID: 2X37
Revision 1.0Jun 16, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_entry_details.has_protein_modification / _struct_conn.pdbx_leaving_atom_flag / _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: RAC-BETA SERINE/THREONINE-PROTEIN KINASE
C: GLYCOGEN SYNTHASE KINASE-3 BETA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3483
Polymers40,9842
Non-polymers3651
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-1.8 kcal/mol
Surface area15330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.948, 61.233, 135.671
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 / 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 / Mutation: YES
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) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P31751, non-specific serine/threonine protein kinase
#2: Protein/peptide GLYCOGEN SYNTHASE KINASE-3 BETA / GSK-3 BETA / 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-X37 / 4-(4-tert-butylbenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium


Mass: 364.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H30N5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
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.

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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: 2.28 Å3/Da / Density % sol: 46 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723
DetectorType: RAYONIX / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.72→55.8 Å / Num. obs: 10369 / % possible obs: 98 % / Observed criterion σ(I): 0 / Redundancy: 2.2 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 4.9
Reflection shellResolution: 2.72→2.97 Å / Rmerge(I) obs: 0.29 / Mean I/σ(I) obs: 2.4 / % possible all: 95

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Processing

Software
NameVersionClassification
REFMAC5.6.0062refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→67.42 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.833 / SU B: 30.523 / SU ML: 0.311 / Cross valid method: THROUGHOUT / ESU R Free: 0.451 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.30537 492 4.8 %RANDOM
Rwork0.21133 ---
obs0.21574 9800 97.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.411 Å2
Baniso -1Baniso -2Baniso -3
1--0.44 Å20 Å20 Å2
2--3.56 Å20 Å2
3----3.11 Å2
Refinement stepCycle: LAST / Resolution: 2.72→67.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2670 0 27 44 2741
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222761
X-RAY DIFFRACTIONr_bond_other_d0.0020.021940
X-RAY DIFFRACTIONr_angle_refined_deg1.4381.963728
X-RAY DIFFRACTIONr_angle_other_deg0.8932.9754677
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6685.092326
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.37823.059136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.32515.041490
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4941522
X-RAY DIFFRACTIONr_chiral_restr0.0810.2393
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023030
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02610
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.724→2.795 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 32 -
Rwork0.275 682 -
obs--92.37 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.03450.1747-0.86962.4650.68442.9434-0.04880.44880.1166-0.33370.01860.17920.0454-0.09780.03020.1373-0.0032-0.00320.12660.0410.095639.870437.915106.9277
22.56980.1895-0.08822.4444-0.79312.0152-0.01240.02130.012-0.06130.0152-0.0196-0.0365-0.0058-0.00280.01750.0194-0.00090.0369-0.0260.063637.516929.8977127.6584
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A146 - 231
2X-RAY DIFFRACTION2C3 - 12
3X-RAY DIFFRACTION2A232 - 479

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