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- PDB-6f14: Crystal structure of the cAMP-dependent protein kinase A cocrysta... -

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Basic information

Entry
Database: PDB / ID: 6f14
TitleCrystal structure of the cAMP-dependent protein kinase A cocrystallized with isoquinoline and PKI (5-24)
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE / phosphotransferase / signalling pathways / glycogen metabolism / serine/threonine kinase
Function / homology
Function and homology information


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 / regulation of osteoblast differentiation / sperm capacitation / 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 / regulation of osteoblast differentiation / sperm capacitation / cAMP-dependent protein kinase activity / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / 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 / plasma membrane raft / protein kinase A catalytic subunit binding / axoneme / 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 kinase A signaling / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / neural tube closure / cellular response to glucose stimulus / neuromuscular junction / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / manganese ion binding / cellular response to heat / dendritic spine / regulation of cell cycle / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / glutamatergic synapse / ubiquitin protein ligase binding / protein kinase binding / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / magnesium ion binding / 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
ISOQUINOLINE / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesCricetulus griseus (Chinese hamster)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.867 Å
AuthorsOebbeke, M. / Wienen-Schmidt, B. / Heine, A. / Klebe, G.
CitationJournal: To Be Published
Title: Fragment based drug design - Small chemical changes of fragments effecting big changes in binding
Authors: Oebbeke, M. / Wienen-Schmidt, B. / Gerber, H.-D. / Heine, A. / Klebe, G.
History
DepositionNov 21, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release

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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)43,3124
Polymers43,0652
Non-polymers2472
Water5,062281
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2400 Å2
ΔGint7 kcal/mol
Surface area16050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.747, 75.273, 80.931
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 catalytic subunit alpha / PKA C-alpha


Mass: 40838.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cricetulus griseus (Chinese hamster) / Gene: PRKACA
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
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 / Source: (synth.) Mus musculus (house mouse) / References: UniProt: P63248
#3: Chemical ChemComp-ISQ / ISOQUINOLINE


Mass: 129.159 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H7N / Comment: alkaloid*YM
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / 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 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 30 mM MES-BIS-TRIS-Buffer, 1mM dithiothreitol, 0.1 mM sodium EDTA, 75 mM LiCl, 0.03 mM Mega 8, 10 mM isoquinoline in DMSO, 0.07 mM PKI (5-24) and methanol 24 % (v/v)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.918409 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Mar 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918409 Å / Relative weight: 1
ReflectionResolution: 1.867→43.932 Å / Num. obs: 37501 / % possible obs: 99.8 % / Redundancy: 5.9 % / Rsym value: 0.059 / Net I/σ(I): 21.4
Reflection shellResolution: 1.87→1.98 Å / Mean I/σ(I) obs: 3.7 / Rsym value: 0.495 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHASER(1.10.1_2155: ???)phasing
Coot0.8model building
PHENIX1.10.1-2155refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.867→43.932 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 20.23
RfactorNum. reflection% reflection
Rfree0.2088 1874 5 %
Rwork0.1746 --
obs0.1764 37498 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.867→43.932 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2864 0 18 281 3163
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073042
X-RAY DIFFRACTIONf_angle_d0.7784132
X-RAY DIFFRACTIONf_dihedral_angle_d17.3321798
X-RAY DIFFRACTIONf_chiral_restr0.053441
X-RAY DIFFRACTIONf_plane_restr0.006543
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8669-1.91740.27681400.21192673X-RAY DIFFRACTION99
1.9174-1.97380.24541430.20882727X-RAY DIFFRACTION100
1.9738-2.03750.26051410.20612684X-RAY DIFFRACTION100
2.0375-2.11040.25871420.17762688X-RAY DIFFRACTION100
2.1104-2.19490.22121430.17182720X-RAY DIFFRACTION100
2.1949-2.29470.20991420.17112710X-RAY DIFFRACTION100
2.2947-2.41570.20921450.16842742X-RAY DIFFRACTION100
2.4157-2.5670.20751430.17572719X-RAY DIFFRACTION100
2.567-2.76520.24651440.18712733X-RAY DIFFRACTION100
2.7652-3.04340.22911450.18272763X-RAY DIFFRACTION100
3.0434-3.48370.18771460.182770X-RAY DIFFRACTION100
3.4837-4.38840.18731470.15562787X-RAY DIFFRACTION100
4.3884-43.94430.1841530.16672908X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0569-0.0251-0.04570.01620.01870.02290.1578-0.0325-0.1474-0.0944-0.19070.09370.4176-0.40040.00010.3536-0.1127-0.09690.36110.02570.3077-39.9009-3.9372-17.3795
20.05670.0961-0.08430.2069-0.17530.1512-0.0197-0.00360.08230.09030.04850.0108-0.3033-0.09930.01410.13030.092-0.00230.2627-0.00160.2408-35.138220.8760.229
30.1868-0.17540.10940.1776-0.12890.8161-0.0322-0.01980.0398-0.02510.06010.06660.101-0.10990.00960.101-0.0030.00570.1627-0.00350.1583-29.76556.4705-2.1569
40.15340.05680.1340.3558-0.29210.4229-0.01090.0026-0.0609-0.11-0.0506-0.03250.36840.0897-0.00780.1980.06030.02840.16560.00750.1375-19.5771-3.141-4.0891
50.3151-0.14680.24310.1483-0.11341.03990.1367-0.0663-0.4581-0.09990.0670.2371.0078-0.18940.63480.5721-0.07420.04320.09340.03360.2353-28.232-15.5362-0.8037
60.1747-0.2188-0.07070.21570.04740.1571-0.0579-0.08240.10780.09790.0907-0.0857-0.26270.05680.00050.20160.0141-0.01920.2215-0.00720.2082-27.402619.79161.5063
70.0011-0.0010.00290.01-0.00220.0024-0.0536-0.00810.06080.0319-0.10460.006-0.0506-0.0444-00.19930.05850.00950.25360.00110.1758-12.9536-8.173216.2105
80.0091-0.0105-0.00660.01480.01260.009-0.0659-0.1534-0.01860.0907-0.0805-0.05550.00760.043100.18980.0585-0.02830.22410.0010.1768-14.63562.68777.5244
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 67 )
3X-RAY DIFFRACTION3chain 'A' and (resid 68 through 160 )
4X-RAY DIFFRACTION4chain 'A' and (resid 161 through 252 )
5X-RAY DIFFRACTION5chain 'A' and (resid 253 through 316 )
6X-RAY DIFFRACTION6chain 'A' and (resid 317 through 350 )
7X-RAY DIFFRACTION7chain 'B' and (resid 5 through 11 )
8X-RAY DIFFRACTION8chain 'B' and (resid 12 through 22 )

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