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

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Basic information

Entry
Database: PDB / ID: 5lcp
TitleCocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with Fasudil (M77)
Components(cAMP-dependent protein kinase ...Protein kinase A) x 2
KeywordsTRANSFERASE / PKA / Kinase / Fasudil / Inhibition / Cocrystal / 3x-Phosphorylated
Function / homology
Function and homology information


negative regulation of cAMP-dependent protein kinase activity / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / sperm capacitation / regulation of osteoblast differentiation ...negative regulation of cAMP-dependent protein kinase activity / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / sperm capacitation / regulation of osteoblast differentiation / cAMP-dependent protein kinase activity / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / protein kinase A regulatory subunit binding / axoneme / protein kinase A catalytic subunit binding / plasma membrane raft / mesoderm formation / sperm flagellum / regulation of proteasomal protein catabolic process / negative regulation of smoothened signaling pathway / positive regulation of gluconeogenesis / negative regulation of TORC1 signaling / regulation of G2/M transition of mitotic cell cycle / protein export from nucleus / protein serine/threonine/tyrosine kinase activity / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / cellular response to glucose stimulus / neuromuscular junction / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / cellular response to heat / manganese ion binding / dendritic spine / regulation of cell cycle / nuclear speck / protein domain specific binding / phosphorylation / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / glutamatergic synapse / ubiquitin protein ligase binding / protein kinase binding / perinuclear region of cytoplasm / magnesium ion binding / negative regulation of transcription by RNA polymerase II / mitochondrion / ATP binding / nucleus / 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
5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE / 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: 1.433 Å
AuthorsWienen-Schmidt, B. / Heine, A. / Klebe, G.
Funding support Belgium, 1items
OrganizationGrant numberCountry
European Research Council268145 - Project Acronym: DrugProfilBind Belgium
CitationJournal: To Be Published
Title: Cocrystal structure of cAMP-dependent Protein Kinase (PKA) in complex with Fasudil (M77)
Authors: Wienen-Schmidt, 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 ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)43,8709
Polymers43,3402
Non-polymers5307
Water7,855436
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-1 kcal/mol
Surface area17030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.394, 72.832, 109.272
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 / CAMP-dependent pathway / 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 / CAMP-dependent pathway / 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)
Source: (synth.) Homo sapiens (human) / References: UniProt: P61925

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Non-polymers , 4 types, 443 molecules

#3: Chemical ChemComp-M77 / 5-(1,4-DIAZEPAN-1-SULFONYL)ISOQUINOLINE / Fasudil / (5-ISOQUINOLINESULFONYL)HOMOPIPERAZINE / Fasudil


Mass: 291.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17N3O2S / Comment: inhibitor*YM
#4: Chemical
ChemComp-MOH / METHANOL / Methanol


Mass: 32.042 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CH4O
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 436 / 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: 2.15 Å3/Da / Density % sol: 54.12 %
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 (50 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 (50 mM Stock) Reservoir: 18% 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 23, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.43→50 Å / Num. obs: 84420 / % possible obs: 97.9 % / Redundancy: 4 % / Rsym value: 0.041 / Net I/σ(I): 17.09
Reflection shellResolution: 1.43→1.52 Å / Redundancy: 3.97 % / Rmerge(I) obs: 0.466 / Mean I/σ(I) obs: 2.49 / % possible all: 95.8

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Processing

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

1q8w


Resolution: 1.433→39.896 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 14.67
RfactorNum. reflection% reflection
Rfree0.1659 4223 5 %
Rwork0.1327 --
obs0.1344 84413 97.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.433→39.896 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2979 0 34 436 3449
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083246
X-RAY DIFFRACTIONf_angle_d0.9444416
X-RAY DIFFRACTIONf_dihedral_angle_d18.2571199
X-RAY DIFFRACTIONf_chiral_restr0.074467
X-RAY DIFFRACTIONf_plane_restr0.007587
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4326-1.44890.28311260.22522405X-RAY DIFFRACTION89
1.4489-1.46590.22291380.19462630X-RAY DIFFRACTION98
1.4659-1.48380.21851410.18242634X-RAY DIFFRACTION98
1.4838-1.50260.22171390.16762645X-RAY DIFFRACTION98
1.5026-1.52240.21411360.1622624X-RAY DIFFRACTION97
1.5224-1.54320.22161400.1552624X-RAY DIFFRACTION97
1.5432-1.56530.16211400.14292627X-RAY DIFFRACTION98
1.5653-1.58860.19241370.13562631X-RAY DIFFRACTION97
1.5886-1.61340.19131400.13122664X-RAY DIFFRACTION98
1.6134-1.63990.15741390.12522646X-RAY DIFFRACTION98
1.6399-1.66820.15541410.11972674X-RAY DIFFRACTION98
1.6682-1.69850.17161390.12422643X-RAY DIFFRACTION98
1.6985-1.73120.18481430.12472689X-RAY DIFFRACTION99
1.7312-1.76650.17181390.11632667X-RAY DIFFRACTION99
1.7665-1.80490.14221390.11792659X-RAY DIFFRACTION98
1.8049-1.84690.16561420.11692671X-RAY DIFFRACTION98
1.8469-1.89310.15681420.12012692X-RAY DIFFRACTION99
1.8931-1.94430.17151420.12492710X-RAY DIFFRACTION99
1.9443-2.00150.1751410.12812664X-RAY DIFFRACTION98
2.0015-2.06610.16041410.13292710X-RAY DIFFRACTION99
2.0661-2.13990.17471440.13422691X-RAY DIFFRACTION99
2.1399-2.22560.1721410.12612691X-RAY DIFFRACTION98
2.2256-2.32690.16551420.1222693X-RAY DIFFRACTION99
2.3269-2.44950.13341430.12212704X-RAY DIFFRACTION99
2.4495-2.6030.16191430.1232717X-RAY DIFFRACTION98
2.603-2.80390.15441430.13182716X-RAY DIFFRACTION98
2.8039-3.0860.16741420.13592696X-RAY DIFFRACTION98
3.086-3.53230.16811430.14012721X-RAY DIFFRACTION98
3.5323-4.44940.15211460.12722775X-RAY DIFFRACTION98
4.4494-39.91140.16221510.14062877X-RAY DIFFRACTION97

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