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- PDB-6e99: Crystal structure of Protein Kinase A in complex with the PKI pep... -

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Basic information

Entry
Database: PDB / ID: 6.0E+99
TitleCrystal structure of Protein Kinase A in complex with the PKI peptide and an amino-pyridinylbenzamide based inhibitor.
Components
  • PKI peptide
  • cAMP-dependent protein kinase catalytic subunit alpha
KeywordsTRANSFERASE / Protein Kinase A / kinase
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 / negative regulation of cAMP-dependent protein kinase activity / VEGFA-VEGFR2 Pathway / 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-J0G / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.88 Å
AuthorsJudge, R.A. / Hobson, A.D.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design.
Authors: Hobson, A.D. / Judge, R.A. / Aguirre, A.L. / Brown, B.S. / Cui, Y. / Ding, P. / Dominguez, E. / DiGiammarino, E. / Egan, D.A. / Freiberg, G.M. / Gopalakrishnan, S.M. / Harris, C.M. / Honore, ...Authors: Hobson, A.D. / Judge, R.A. / Aguirre, A.L. / Brown, B.S. / Cui, Y. / Ding, P. / Dominguez, E. / DiGiammarino, E. / Egan, D.A. / Freiberg, G.M. / Gopalakrishnan, S.M. / Harris, C.M. / Honore, M.P. / Kage, K.L. / Kapecki, N.J. / Ling, C. / Ma, J. / Mack, H. / Mamo, M. / Maurus, S. / McRae, B. / Moore, N.S. / Mueller, B.K. / Mueller, R. / Namovic, M.T. / Patel, K. / Pratt, S.D. / Putman, C.B. / Queeney, K.L. / Sarris, K.K. / Schaffter, L.M. / Stoll, V.S. / Vasudevan, A. / Wang, L. / Wang, L. / Wirthl, W. / Yach, K.
History
DepositionJul 31, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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: cAMP-dependent protein kinase catalytic subunit alpha
B: PKI peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,2013
Polymers42,8112
Non-polymers3901
Water8,179454
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: Made complex prior to crystallization. Electron density maps showed clear presence of the peptide
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-5 kcal/mol
Surface area16980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.665, 80.632, 103.865
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 40837.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: PRKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: Protein/peptide PKI peptide / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 1973.177 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical ChemComp-J0G / 2-[(2-aminoethyl)amino]-N-[(1R)-1-(3-methoxyphenyl)ethyl]-4-(pyridin-4-yl)benzamide


Mass: 390.478 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 454 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.05 Å3/Da / Density % sol: 59.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.6 / Details: 5 to 27% methanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Oct 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→63.69 Å / Num. obs: 40178 / % possible obs: 96.7 % / Redundancy: 4.6 % / Biso Wilson estimate: 32.18 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.033 / Rpim(I) all: 0.017 / Rrim(I) all: 0.037 / Net I/σ(I): 29.2
Reflection shellResolution: 1.88→1.98 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.338 / Num. unique obs: 4918 / CC1/2: 0.902 / Rpim(I) all: 0.225 / Rrim(I) all: 0.408 / % possible all: 82.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
Aimless0.6.3data scaling
MOLREPphasing
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→27.02 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.14 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.134 / SU Rfree Cruickshank DPI: 0.127
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1992 4.97 %RANDOM
Rwork0.207 ---
obs0.208 40109 96.5 %-
Displacement parametersBiso max: 109.52 Å2 / Biso mean: 34.52 Å2 / Biso min: 14.99 Å2
Baniso -1Baniso -2Baniso -3
1--10.5536 Å20 Å20 Å2
2--5.1397 Å20 Å2
3---5.4139 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.88→27.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2892 0 29 454 3375
Biso mean--29.39 45.71 -
Num. residues----351
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1049SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes517HARMONIC5
X-RAY DIFFRACTIONt_it3023HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion370SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3315SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3023HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4098HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion2.61
X-RAY DIFFRACTIONt_other_torsion17.62
LS refinement shellResolution: 1.88→1.9 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3715 42 5.23 %
Rwork0.3174 761 -
all0.3201 803 -
obs--75.61 %

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