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- PDB-5lcr: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in com... -

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Basic information

Entry
Database: PDB / ID: 5lcr
TitleCocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with open-chain Fasudil-derivative (Ligand 04)
Components(cAMP-dependent protein kinase ...) x 2
KeywordsTRANSFERASE / PKA / Kinase / Fasudil-derivative / Inhibition / Cocrystal / 3x-Phosphorylated / Ligand 10
Function / homology
Function and homology information


negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus ...negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / negative regulation of protein import into nucleus / regulation of osteoblast differentiation / cellular response to cold / sperm capacitation / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / intracellular potassium ion homeostasis / mesoderm formation / plasma membrane raft / axoneme / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of G2/M transition of mitotic cell cycle / negative regulation of TORC1 signaling / regulation of proteasomal protein catabolic process / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / acrosomal vesicle / protein export from nucleus / positive regulation of phagocytosis / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / neuromuscular junction / cellular response to glucose stimulus / positive regulation of cholesterol biosynthetic process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / adenylate cyclase-activating G protein-coupled receptor signaling pathway / manganese ion binding / cellular response to heat / postsynapse / regulation of cell cycle / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / centrosome / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / magnesium ion binding / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / cytoplasm / cytosol
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. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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. / 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-6TX / METHANOL / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.565 Å
AuthorsWienen-Schmidt, B. / Heine, A. / Klebe, G.
Funding support1items
OrganizationGrant numberCountry
European Research Council268145 - Project Acronym: DrugProfilBind
CitationJournal: To Be Published
Title: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with different Fasudil-derivatives
Authors: Wienen, B. / Jonker, H.R.A. / Wulsdorf, T. / Gerber, H.-D. / Saxena, K. / Kudlinzki, D. / Sreeramulu, S. / Parigi, G. / Luchinat, C. / Heine, A. / Schwalbe, H. / Klebe, G.
History
DepositionJun 22, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9139
Polymers43,3402
Non-polymers5737
Water6,774376
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-5 kcal/mol
Surface area16730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.279, 72.840, 108.727
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 kinase ... , 2 types, 2 molecules AB

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


Mass: 41113.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Phosphorylated at Ser11, Thr198, Ser339 / Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: PRKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P25321, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / PKI-alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform


Mass: 2226.411 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Amino acids 5-24 from cAMP-dependent protein kinase inhibitor alpha from Sigma (order ID: P7739); the last amino acid is not well defined in the crystal structure
Source: (synth.) Homo sapiens (human) / References: UniProt: P61925

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Non-polymers , 4 types, 383 molecules

#3: Chemical ChemComp-6TX / 2-[isoquinolin-5-ylsulfonyl(propyl)amino]ethylazanium


Mass: 294.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N3O2S
#4: Chemical ChemComp-MRD / (4R)-2-METHYLPENTANE-2,4-DIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Chemical
ChemComp-MOH / METHANOL


Mass: 32.042 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CH4O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.18 Å3/Da / Density % sol: 53.8 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: Drop: 10 mg/ml PKA (0.240 mM) 30 mM MBT (MES/Bis-Tris Puffer pH 6.9) 1 mM DTT 0.1 mM EDTA 75 mM LiCl 0.03 mM Mega 8 0.07mM PKI (Sigma: P7739) 1.2 mM ligand solved in DMSO (100 mM Stock) ...Details: Drop: 10 mg/ml PKA (0.240 mM) 30 mM MBT (MES/Bis-Tris Puffer pH 6.9) 1 mM DTT 0.1 mM EDTA 75 mM LiCl 0.03 mM Mega 8 0.07mM PKI (Sigma: P7739) 1.2 mM ligand solved in DMSO (100 mM Stock) Reservoir: 14% Methanol 0.003 mL drop volume, 0.4 mL reservoir volume

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.56→50 Å / Num. obs: 64829 / % possible obs: 98.3 % / Redundancy: 4 % / Rsym value: 0.068 / Net I/σ(I): 11.24
Reflection shellResolution: 1.56→1.66 Å / Redundancy: 4 % / Rmerge(I) obs: 0.491 / Mean I/σ(I) obs: 2.12 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Q8W

1q8w


Resolution: 1.565→39.753 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 17.65
RfactorNum. reflection% reflection
Rfree0.1965 3243 5 %
Rwork0.1549 --
obs0.157 64825 98.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.565→39.753 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2964 0 38 376 3378
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083128
X-RAY DIFFRACTIONf_angle_d0.9794242
X-RAY DIFFRACTIONf_dihedral_angle_d16.0541850
X-RAY DIFFRACTIONf_chiral_restr0.055450
X-RAY DIFFRACTIONf_plane_restr0.007559
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.565-1.58830.2551280.19792424X-RAY DIFFRACTION90
1.5883-1.61320.26081390.18612644X-RAY DIFFRACTION99
1.6132-1.63960.24351420.17742671X-RAY DIFFRACTION99
1.6396-1.66790.23511390.16762637X-RAY DIFFRACTION98
1.6679-1.69820.23171400.16862656X-RAY DIFFRACTION99
1.6982-1.73090.20811380.16332646X-RAY DIFFRACTION99
1.7309-1.76620.23081430.16592699X-RAY DIFFRACTION99
1.7662-1.80460.22221370.16942649X-RAY DIFFRACTION99
1.8046-1.84660.23091420.16442667X-RAY DIFFRACTION99
1.8466-1.89280.21771410.15772696X-RAY DIFFRACTION99
1.8928-1.94390.22041420.15662679X-RAY DIFFRACTION99
1.9439-2.00110.20391400.15152658X-RAY DIFFRACTION99
2.0011-2.06570.21161400.15912690X-RAY DIFFRACTION99
2.0657-2.13950.19481440.15612703X-RAY DIFFRACTION99
2.1395-2.22520.19351400.15332679X-RAY DIFFRACTION99
2.2252-2.32650.19081420.14152703X-RAY DIFFRACTION99
2.3265-2.44910.18481420.1492680X-RAY DIFFRACTION99
2.4491-2.60250.21181420.15532691X-RAY DIFFRACTION98
2.6025-2.80340.20221420.16012697X-RAY DIFFRACTION98
2.8034-3.08540.22231430.16032698X-RAY DIFFRACTION99
3.0854-3.53170.18151430.15732713X-RAY DIFFRACTION98
3.5317-4.44860.17531440.13912744X-RAY DIFFRACTION98
4.4486-39.76580.16261500.15232858X-RAY DIFFRACTION97

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