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- PDB-2vo6: Structure of PKA-PKB chimera complexed with 4-(4-Chlorobenzyl)-1-... -

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Basic information

Entry
Database: PDB / ID: 2vo6
TitleStructure of PKA-PKB chimera complexed with 4-(4-Chlorobenzyl)-1-(7H- pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-ylamine
Components
  • CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHACAMP-dependent pathway
  • CAMP-DEPENDENT PROTEIN KINASE, ALPHA-CATALYTIC SUBUNITCAMP-dependent pathway
KeywordsTRANSFERASE / LIPOPROTEIN / ATP-BINDING / PHOSPHOPROTEIN / SERINE/THREONINE-PROTEIN KINASE / NUCLEOTIDE-BINDING / PROTEIN KINASE INHIBITOR / CAMP / KINASE / NUCLEUS / MYRISTATE / CYTOPLASM
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 / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of protein import into nucleus / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / mesoderm formation / sperm flagellum / protein kinase A signaling / negative regulation of TORC1 signaling / regulation of G2/M transition of mitotic cell cycle / acrosomal vesicle / neuromuscular junction / cellular response to heat / peptidyl-serine phosphorylation / 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-M05 / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesBOS TAURUS (cattle)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsCaldwell, J.J. / Davies, T.G. / Donald, A. / McHardy, T. / Rowlands, M.G. / Aherne, G.W. / Hunter, L.K. / Taylor, K. / Ruddle, R. / Raynaud, F.I. ...Caldwell, J.J. / Davies, T.G. / Donald, A. / McHardy, T. / Rowlands, M.G. / Aherne, G.W. / Hunter, L.K. / Taylor, K. / Ruddle, R. / Raynaud, F.I. / Verdonk, M. / Workman, P. / Garrett, M.D. / Collins, I.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Identification of 4-(4-Aminopiperidin-1-Yl)-7H-Pyrrolo[2,3-D]Pyrimidines as Selective Inhibitors of Protein Kinase B Through Fragment Elaboration.
Authors: Caldwell, J.J. / Davies, T.G. / Donald, A. / Mchardy, T. / Rowlands, M.G. / Aherne, G.W. / Hunter, L.K. / Taylor, K. / Ruddle, R. / Raynaud, F.I. / Verdonk, M. / Workman, P. / Garrett, M.D. / Collins, I.
History
DepositionFeb 8, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2008Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CAMP-DEPENDENT PROTEIN KINASE, ALPHA-CATALYTIC SUBUNIT
I: CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5154
Polymers43,1372
Non-polymers3782
Water7,909439
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2320 Å2
ΔGint-5.5 kcal/mol
Surface area19720 Å2
MethodPQS
Unit cell
Length a, b, c (Å)72.910, 74.291, 80.104
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 / CAMP-dependent pathway / PKA C-ALPHA / PROTEIN KINASE A


Mass: 40910.598 Da / Num. of mol.: 1 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (cattle) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: Protein/peptide CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA / CAMP-dependent pathway / PKI-ALPHA / CAMP- DEPENDENT PROTEIN KINASE INHIBITOR / MUSCLE/BRAIN ISOFORM / PKI


Mass: 2226.411 Da / Num. of mol.: 1 / Fragment: RESIDUES 6-25 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P61925
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-M05 / 4-(4-chlorobenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium


Mass: 342.846 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21ClN5
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 439 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, VAL 105 TO THR ENGINEERED RESIDUE IN CHAIN A, VAL 124 TO ALA ...ENGINEERED RESIDUE IN CHAIN A, VAL 105 TO THR ENGINEERED RESIDUE IN CHAIN A, VAL 124 TO ALA ENGINEERED RESIDUE IN CHAIN A, LEU 174 TO MET ENGINEERED RESIDUE IN CHAIN A, GLN 182 TO LYS
Sequence details4 RESIDUES OF THE WILD-TYPE PKA SEQUENCE HAVE BEEN MUTATED TO THE CORRESPONDING RESIDUES IN PKB

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.26 Å3/Da / Density % sol: 45.17 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.97→26 Å / Num. obs: 28840 / % possible obs: 97.1 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.04
Reflection shellResolution: 1.97→2.09 Å / Rmerge(I) obs: 0.13 / Mean I/σ(I) obs: 5.1 / % possible all: 90.5

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Processing

SoftwareName: REFMAC / Version: 5.2.0019I / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.97→26.02 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.922 / SU B: 3.616 / SU ML: 0.104 / Cross valid method: THROUGHOUT / ESU R: 0.165 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ALTHOUGH THERE IS EVIDENCE FOR A SECOND INHIBITOR BINDING SITE NEAR LYS 292, ONLY THE PYRROLO- PYRIMIDINE MOIETY COULD BE FITTED WITH ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ALTHOUGH THERE IS EVIDENCE FOR A SECOND INHIBITOR BINDING SITE NEAR LYS 292, ONLY THE PYRROLO- PYRIMIDINE MOIETY COULD BE FITTED WITH CONFIDENCE, AND SO THIS SITE HAS NOT BEEN BUILT IN THE FINAL MODEL.
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1536 5.1 %RANDOM
Rwork0.172 ---
obs0.175 28840 97.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.33 Å2
Baniso -1Baniso -2Baniso -3
1-0.89 Å20 Å20 Å2
2---0.15 Å20 Å2
3----0.74 Å2
Refinement stepCycle: LAST / Resolution: 1.97→26.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2954 0 25 439 3418
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0223066
X-RAY DIFFRACTIONr_bond_other_d0.0010.022144
X-RAY DIFFRACTIONr_angle_refined_deg1.3241.9534143
X-RAY DIFFRACTIONr_angle_other_deg0.892.9955194
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4995358
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.34623.845155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.20115.082550
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6851518
X-RAY DIFFRACTIONr_chiral_restr0.0850.2426
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023359
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02663
X-RAY DIFFRACTIONr_nbd_refined0.2090.2614
X-RAY DIFFRACTIONr_nbd_other0.1940.22247
X-RAY DIFFRACTIONr_nbtor_refined0.1860.21505
X-RAY DIFFRACTIONr_nbtor_other0.0860.21514
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1050.283
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1460.24
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3440.221
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.070.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.09451786
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.12162883
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.11561280
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.1437.51259
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: 1.97→2.02 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.259 102
Rwork0.208 1837

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