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- PDB-1sve: Crystal Structure of Protein Kinase A in Complex with Azepane Der... -

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Basic information

Entry
Database: PDB / ID: 1sve
TitleCrystal Structure of Protein Kinase A in Complex with Azepane Derivative 1
Components(cAMP-dependent protein ...) x 2
KeywordsTRANSFERASE / KINASE-INHIBITOR-COMPLEX / SERINE/THREONINE-PROTEIN KINASE / BALANOL DERIVATIVE
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 / AURKA Activation by TPX2 / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / VEGFA-VEGFR2 Pathway / PKA activation / negative regulation of cAMP-dependent protein kinase activity / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / 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 / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / negative regulation of protein import into nucleus / Vasopressin regulates renal water homeostasis via Aquaporins / molecular function inhibitor activity / 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 / molecular adaptor activity / protein kinase activity / protein domain specific binding / protein phosphorylation / 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-I01 / N-OCTANOYL-N-METHYLGLUCAMINE / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesBos taurus (cattle)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsBreitenlechner, C.B. / Wegge, T. / Berillon, L. / Graul, K. / Marzenell, K. / Friebe, W.-G. / Thomas, U. / Schumacher, R. / Huber, R. / Engh, R.A. / Masjost, B.
CitationJournal: 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
DepositionMar 29, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Remark 600HETEROGEN Only part of MG8 molecule is visible in the electron density.

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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)43,8655
Polymers43,0132
Non-polymers8523
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3210 Å2
ΔGint-23 kcal/mol
Surface area16490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.240, 76.320, 79.740
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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CAMP-dependent protein ... , 2 types, 2 molecules AB

#1: Protein cAMP-dependent protein kinase, alpha-catalytic subunit / PKA C-alpha / PROTEIN KINASE A


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 / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 1 / Fragment: RESIDUES 5-24 / Source method: obtained synthetically
Details: The peptide was chemically synthesized. The sequence of the peptide occurs naturally in humans.
References: UniProt: P04541, UniProt: P61926*PLUS

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Non-polymers , 4 types, 101 molecules

#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-I01 / (4R)-4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-BENZOIC ACID (3R)-3-[(PYRIDINE-4-CARBONYL)AMINO]-AZEPAN-4-YL ESTER


Mass: 507.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26FN3O6
#5: Chemical ChemComp-MG8 / N-OCTANOYL-N-METHYLGLUCAMINE / MEGA 8, N-(D-GLUCITYL)-N-METHYLOCTANAMIDE


Mass: 321.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H31NO6
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.63 Å3/Da / Density % sol: 53.16 %
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

DiffractionMean temperature: 278 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: SIEMENS X1000 / Detector: AREA DETECTOR / Date: Jun 29, 2001 / Details: GRAPHITE MONOCHROMATOR
RadiationMonochromator: GRAPHITE MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.49→20.93 Å / Num. all: 14845 / Num. obs: 14845 / % possible obs: 91.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.5→2.57 Å / % possible all: 54

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
ASTROdata reduction
SAINTdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.49→20.94 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.87 / SU B: 9.681 / SU ML: 0.212 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.685 / ESU R Free: 0.314 / Stereochemistry target values: Engh & Huber / Details: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.257 757 5.1 %FROM STARTING MODEL
Rwork0.199 ---
all0.202 14088 --
obs0.202 14088 91.06 %-
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: 18.843 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.49→20.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2931 0 46 98 3075
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0213052
X-RAY DIFFRACTIONr_bond_other_d0.0020.022689
X-RAY DIFFRACTIONr_angle_refined_deg1.4771.964130
X-RAY DIFFRACTIONr_angle_other_deg0.82936234
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3465361
X-RAY DIFFRACTIONr_chiral_restr0.0790.2433
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023379
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02660
X-RAY DIFFRACTIONr_nbd_refined0.2130.2582
X-RAY DIFFRACTIONr_nbd_other0.2280.23125
X-RAY DIFFRACTIONr_nbtor_other0.0870.21799
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1710.2101
X-RAY DIFFRACTIONr_metal_ion_refined0.210.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1760.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2950.228
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.150.28
X-RAY DIFFRACTIONr_mcbond_it0.6321.51805
X-RAY DIFFRACTIONr_mcangle_it1.18222899
X-RAY DIFFRACTIONr_scbond_it1.56931247
X-RAY DIFFRACTIONr_scangle_it2.6384.51231
LS refinement shellResolution: 2.494→2.558 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.393 42
Rwork0.292 863

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