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

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Basic information

Entry
Database: PDB / ID: 3oxt
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 / Phosphorylation
Function / homology
Function and homology information


cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction ...cAMP/PKA signal transduction / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / ROBO receptors bind AKAP5 / channel activator activity / HDL assembly / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / mitochondrial protein catabolic process / negative regulation of cAMP-dependent protein kinase activity / negative regulation of cAMP/PKA signal transduction / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / regulation of protein processing / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / regulation of osteoblast differentiation / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / cAMP-dependent protein kinase activity / sperm capacitation / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / cAMP-dependent protein kinase complex / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / AMP-activated protein kinase activity / negative regulation of protein import into nucleus / negative regulation of interleukin-2 production / postsynaptic modulation of chemical synaptic transmission / 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 / Interleukin-3, Interleukin-5 and GM-CSF signaling / DARPP-32 events / regulation of cardiac muscle contraction / regulation of cardiac conduction / sperm flagellum / regulation of macroautophagy / renal water homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / regulation of proteasomal protein catabolic process / negative regulation of smoothened signaling pathway / Ion homeostasis / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / positive regulation of gluconeogenesis / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / cellular response to glucagon stimulus / regulation of G2/M transition of mitotic cell cycle / Anchoring of the basal body to the plasma membrane / calcium channel complex / Mitochondrial protein degradation / cellular response to epinephrine stimulus / protein kinase A signaling / protein serine/threonine/tyrosine kinase activity / protein export from nucleus / CD209 (DC-SIGN) signaling / positive regulation of calcium-mediated signaling / regulation of heart rate / AURKA Activation by TPX2 / FCGR3A-mediated IL10 synthesis / acrosomal vesicle / positive regulation of protein export from nucleus / 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 / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / Vasopressin regulates renal water homeostasis via Aquaporins / mRNA processing / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / manganese ion binding / Factors involved in megakaryocyte development and platelet production / cellular response to heat / peptidyl-serine phosphorylation / dendritic spine
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-3SB / 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: 2.2 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 22, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2011Provider: 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)43,3343
Polymers43,0352
Non-polymers2991
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1720 Å2
ΔGint-2 kcal/mol
Surface area15410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.760, 73.220, 79.950
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 / References: UniProt: P61925
#3: Chemical ChemComp-3SB / (2S)-2-amino-N'-[(1E)-(2,4-dihydroxy-6-methylphenyl)methylidene]-2-phenylethanehydrazide


Mass: 299.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17N3O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 2.58 Å3/Da / Density % sol: 52.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: 5mM 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 23, 2009 / Details: mirrors
RadiationMonochromator: Bartels Monochromator with dual channel cut crystals (DCCM) in (+--+) geometry
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. all: 22925 / Num. obs: 22925 / % possible obs: 100 % / Redundancy: 4 % / Rsym value: 0.074 / Net I/σ(I): 18.6
Reflection shellResolution: 2.2→2.25 Å / Redundancy: 3.9 % / Mean I/σ(I) obs: 2.9 / Rsym value: 0.444 / % 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: 2.2→27.496 Å / SU ML: 0.29 / σ(F): 0 / Phase error: 22.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2391 1044 4.84 %
Rwork0.1731 --
obs0.1763 21592 93.12 %
all-21592 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 33.637 Å2 / ksol: 0.303 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-3.8312 Å2-0 Å2-0 Å2
2---1.7028 Å20 Å2
3----2.1285 Å2
Refinement stepCycle: LAST / Resolution: 2.2→27.496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2836 0 22 232 3090
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082933
X-RAY DIFFRACTIONf_angle_d1.0973976
X-RAY DIFFRACTIONf_dihedral_angle_d14.7541050
X-RAY DIFFRACTIONf_chiral_restr0.071424
X-RAY DIFFRACTIONf_plane_restr0.004509
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.3160.3131200.20682274X-RAY DIFFRACTION74
2.316-2.4610.30831300.19552841X-RAY DIFFRACTION91
2.461-2.65090.26311550.18622897X-RAY DIFFRACTION93
2.6509-2.91740.26641440.17973010X-RAY DIFFRACTION96
2.9174-3.33890.27161570.18433095X-RAY DIFFRACTION98
3.3389-4.20420.22291780.16143156X-RAY DIFFRACTION100
4.2042-27.49810.191600.15773275X-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)
10.08890.10970.27860.30410.3680.95210.0354-0.0457-0.0766-0.06540.0019-0.17190.09520.3318-0.02810.05270.04230.060.16060.00870.129436.7531-14.4262-4.5923
20.2879-0.0605-0.09230.720.60721.0556-0.0163-0.04390.0092-0.0551-0.0305-0.0256-0.13020.05580.03720.06120.0007-0.02440.09690.01710.089125.8223-1.5487-3.1629
30.8864-0.3410.0690.97770.39441.5002-0.0446-0.06770.148-0.19380.0143-0.0596-0.37620.04920.00670.1521-0.0331-0.00520.10670.00460.08428.90583.0619-0.2109
40.00670.0046-0.00760.0033-0.00510.0081-0.0555-0.1060.03720.07090.0285-0.10550.0251-0.1159-0.00010.19360.0123-0.0060.2882-0.00480.198412.80726.449115.3396
50.01360.0044-0.0040.0155-0.00680.0033-0.36910.2545-0.26130.030.11670.11360.1842-0.171300.23720.0232-0.01490.2510.01910.198416.2278-3.53285.0215
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(CHAIN A AND RESID 16:72)
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 5:14)
5X-RAY DIFFRACTION5(CHAIN B AND RESID 15:22)

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