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- PDB-1xh4: Crystal Structures of Protein Kinase B Selective Inhibitors in Co... -

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Basic information

Entry
Database: PDB / ID: 1xh4
TitleCrystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants
Components
  • cAMP-dependent protein kinase inhibitor, alpha form
  • cAMP-dependent protein kinase, alpha-catalytic subunit
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PKA / kinase-inhibitor-complex / serine/threonine-protein kinase / balanol derivative / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production ...CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Anchoring of the basal body to the plasma membrane / RET signaling / AURKA Activation by TPX2 / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / VEGFA-VEGFR2 Pathway / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / PKA activation / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cAMP-dependent protein kinase activity / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Mitochondrial protein degradation / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / sperm flagellum / negative regulation of TORC1 signaling / regulation of G2/M transition of mitotic cell cycle / protein kinase A signaling / acrosomal vesicle / neuromuscular junction / cellular response to heat / peptidyl-serine phosphorylation / protein kinase activity / protein phosphorylation / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase inhibitor / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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-R69 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesBos taurus (cattle)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsBreitenlechner, C.B. / Friebe, W.-G. / Brunet, E. / Werner, G. / Graul, K. / Thomas, U. / Kuenkele, K.-P. / Schaefer, W. / Gassel, M. / Bossemeyer, D. ...Breitenlechner, C.B. / Friebe, W.-G. / Brunet, E. / Werner, G. / Graul, K. / Thomas, U. / Kuenkele, K.-P. / Schaefer, W. / Gassel, M. / Bossemeyer, D. / Huber, R. / Engh, R.A. / Masjost, B.
Citation
Journal: J.Med.Chem. / Year: 2005
Title: Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants
Authors: Breitenlechner, C.B. / Friebe, W.-G. / Brunet, E. / Werner, G. / Graul, K. / Thomas, U. / Kuenkele, K.-P. / Schaefer, W. / Gassel, M. / Bossemeyer, D. / Huber, R. / Engh, R.A. / Masjost, B.
#1: Journal: J.Med.Chem. / Year: 2004
Title: Structure-based optimization of novel azepane derivatives as PKB inhibitors
Authors: Breitenlechner, C.B. / Wegge, T. / Berillon, L. / Graul, K. / Marzenell, K. / Friebe, W.-G. / Thomas, U. / Schumacher, R. / Huber, R. / Engh, R.A. / Masjost, B.
History
DepositionSep 17, 2004Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Sep 17, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jun 26, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entity_src_syn / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / 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_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _struct_conn.pdbx_leaving_atom_flag / _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: cAMP-dependent protein kinase, alpha-catalytic subunit
B: cAMP-dependent protein kinase inhibitor, alpha form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5143
Polymers43,0132
Non-polymers5021
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3240 Å2
ΔGint-19 kcal/mol
Surface area15730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.013, 79.144, 79.643
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 cAMP-dependent protein kinase, alpha-catalytic subunit / Protein Kinase A / PKA C-alpha


Mass: 40786.395 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: PRKACA / Plasmid: pT7-7 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21DE3 / References: UniProt: P00517, EC: 2.7.1.37
#2: Protein/peptide cAMP-dependent protein kinase inhibitor, alpha form / Protein Kinase Inhibitor Peptide / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 1 / Fragment: PKI(residues 5-24) / Source method: obtained synthetically / Details: Peptide synthesis / Source: (synth.) synthetic construct (others) / References: UniProt: P61925
#3: Chemical ChemComp-R69 / N-[4-({4-[5-(DIMETHYLAMINO)-2-HYDROXYBENZOYL]BENZOYL}AMINO)AZEPAN-3-YL]ISONICOTINAMIDE


Mass: 501.577 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H31N5O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / 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: 2.64 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: LiCl, MesBisTris, methanol, MEGA-8, pH 6.4, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: May 20, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.45→33.15 Å / Num. all: 17272 / Num. obs: 17272

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MOSFLMdata reduction
CCP4(SCALA)data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→33.15 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.899 / SU B: 6.899 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.399 / ESU R Free: 0.26 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24152 859 5 %RANDOM
Rwork0.18863 ---
obs0.1912 16412 98.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 27.266 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å20 Å20 Å2
2---0.41 Å20 Å2
3---0.58 Å2
Refinement stepCycle: LAST / Resolution: 2.45→33.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2884 0 37 115 3036
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0212998
X-RAY DIFFRACTIONr_bond_other_d0.0020.022658
X-RAY DIFFRACTIONr_angle_refined_deg1.6221.964061
X-RAY DIFFRACTIONr_angle_other_deg0.91936155
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5235355
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0990.2427
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023324
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02644
X-RAY DIFFRACTIONr_nbd_refined0.210.2580
X-RAY DIFFRACTIONr_nbd_other0.2350.23008
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0880.21674
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2132
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0770.24
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2720.221
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1780.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it0.7471.51775
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.37822855
X-RAY DIFFRACTIONr_scbond_it2.03631223
X-RAY DIFFRACTIONr_scangle_it3.2964.51206
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.45→2.514 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.3 37
Rwork0.201 1138

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