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- PDB-3owp: Human cAMP-dependent protein kinase in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 3owp
TitleHuman cAMP-dependent protein kinase in complex with an inhibitor
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE/TRANSFERASE inhibitor / TRANSFERASE / ATP Binding / Phosphorylation / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / negative regulation of cAMP-dependent protein kinase activity / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly ...PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / HDL assembly / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / negative regulation of cAMP-dependent protein kinase activity / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly / Rap1 signalling / renal water homeostasis / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cell communication by electrical coupling involved in cardiac conduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / 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 / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / PKA activation in glucagon signalling / : / Regulation of MECP2 expression and activity / mesoderm formation / RET signaling / DARPP-32 events / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of cardiac muscle contraction / regulation of cardiac conduction / sperm flagellum / regulation of macroautophagy / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / negative regulation of smoothened signaling pathway / regulation of proteasomal protein catabolic process / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of gluconeogenesis / Recruitment of mitotic centrosome proteins and complexes / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / protein kinase A signaling / Mitochondrial protein degradation / calcium channel complex / Anchoring of the basal body to the plasma membrane / cellular response to epinephrine stimulus / regulation of cytosolic calcium ion concentration / regulation of G2/M transition of mitotic cell cycle / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / regulation of heart rate / CD209 (DC-SIGN) signaling / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / positive regulation of protein export from nucleus / acrosomal vesicle / neural tube closure / Regulation of insulin secretion / cellular response to glucose stimulus / Degradation of GLI1 by the proteasome / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / neuromuscular junction / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / mRNA processing / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / Factors involved in megakaryocyte development and platelet production / cellular response to heat / manganese ion binding / peptidyl-serine phosphorylation / dendritic spine / regulation of cell cycle
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-2SB / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsKoester, H. / Heine, A. / Klebe, G.
CitationJournal: To be Published
Title: fragment based drug design on PKA
Authors: Koester, H. / Craan, T. / Brass, S. / Heine, A. / Klebe, G.
History
DepositionSep 20, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Other
Revision 1.2Mar 13, 2013Group: Other

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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)43,3833
Polymers43,0352
Non-polymers3481
Water5,639313
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1920 Å2
ΔGint-4 kcal/mol
Surface area15420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.890, 75.660, 79.970
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: 40808.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKACA, PRKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P17612, 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 / Fragment: residues 5-24 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P61925
#3: Chemical ChemComp-2SB / (2S)-2-amino-N'-[(1E)-(3-bromo-4-hydroxyphenyl)methylidene]-2-phenylethanehydrazide


Mass: 348.195 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14BrN3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.56 Å3/Da / Density % sol: 51.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: 5 mM MES, 5mM BisTris-propane, 75mM LiCl, 1mM DTT, 0.1 mM EDTA, equilibrated against water/ethanol, pH 6.9, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 22, 2009 / Details: mirrors
RadiationMonochromator: Bartels Monochromator with dual channel cut crystal (DCCM) in (+--+) geometry
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.88→30 Å / Num. all: 36666 / Num. obs: 36666 / % possible obs: 100 % / Redundancy: 4.1 % / Rsym value: 0.061 / Net I/σ(I): 22.2
Reflection shellResolution: 1.88→1.91 Å / Redundancy: 4 % / Mean I/σ(I) obs: 2.8 / Rsym value: 0.449 / % possible all: 100

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHASERphasing
PHENIX(phenix.refine: 1.6.4_486)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→26.935 Å / SU ML: 0.18 / σ(F): 1 / Phase error: 19.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2113 1742 4.98 %
Rwork0.1695 --
obs0.1717 34995 95.39 %
all-35313 -
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 30.925 Å2 / ksol: 0.304 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.4995 Å20 Å2-0 Å2
2--0.2204 Å20 Å2
3----2.7199 Å2
Refinement stepCycle: LAST / Resolution: 1.88→26.935 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2852 0 21 313 3186
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073010
X-RAY DIFFRACTIONf_angle_d1.0634089
X-RAY DIFFRACTIONf_dihedral_angle_d13.5991090
X-RAY DIFFRACTIONf_chiral_restr0.073435
X-RAY DIFFRACTIONf_plane_restr0.004526
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.93460.27711280.21892435X-RAY DIFFRACTION85
1.9346-1.9970.28641440.20162584X-RAY DIFFRACTION91
1.997-2.06840.21591290.17752670X-RAY DIFFRACTION93
2.0684-2.15120.22481290.17262744X-RAY DIFFRACTION95
2.1512-2.2490.24381390.17942751X-RAY DIFFRACTION96
2.249-2.36750.24411250.1722791X-RAY DIFFRACTION97
2.3675-2.51570.21911660.17642775X-RAY DIFFRACTION97
2.5157-2.70980.2231310.17672827X-RAY DIFFRACTION97
2.7098-2.98220.21191700.18042814X-RAY DIFFRACTION98
2.9822-3.4130.20441650.17432874X-RAY DIFFRACTION99
3.413-4.29720.19141380.1522949X-RAY DIFFRACTION99
4.2972-26.9380.18261780.1543039X-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)
10.07940.00410.15170.12460.18730.21860.0087-0.014-0.0149-0.18750.08660.0030.01270.24450.09320.00860.07020.0320.18240.020.140435.0779-14.8465-4.2459
20.2013-0.13810.07790.38190.28680.7048-0.0478-0.0168-0.0074-0.0467-0.0086-0.0215-0.12310.0295-0.00890.0841-0.0013-0.00850.1020.01210.099524.7063-1.5512-3.1447
30.5316-0.33550.05970.34750.24330.6879-0.0825-0.03960.057-0.09190.0801-0.0721-0.18150.0839-0.01060.1846-0.0269-0.00670.09030.00760.108527.95673.3168-0.2629
40.0327-0.0029-0.00250.0093-0.02330.0227-0.01140.05890.0227-0.0056-0.11780.024-0.0405-0.075100.15130.04260.00750.1720.00530.12614.03111.1299.5473
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND RESID 14:72)
2X-RAY DIFFRACTION2(CHAIN A AND RESID 73:251)
3X-RAY DIFFRACTION3(CHAIN A AND RESID 252:350)
4X-RAY DIFFRACTION4(CHAIN B AND RESID 5:23)

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