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- PDB-3l9l: Crystal structure of pka with compound 36 -

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Basic information

Entry
Database: PDB / ID: 3l9l
TitleCrystal structure of pka with compound 36
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PKB / inhibitor / 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 / 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 / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction ...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 / nucleotide-activated protein kinase complex / cell communication by electrical coupling involved in cardiac conduction / high-density lipoprotein particle assembly / Rap1 signalling / negative regulation of cAMP/PKA signal transduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / Loss of phosphorylation of MECP2 at T308 / cAMP-dependent protein kinase activity / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / 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 / negative regulation of interleukin-2 production / cellular response to cold / regulation of osteoblast differentiation / sperm capacitation / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / Triglyceride catabolism / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / cAMP/PKA signal transduction / PKA activation in glucagon signalling / mesoderm formation / RET signaling / Regulation of MECP2 expression and activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / sperm flagellum / plasma membrane raft / DARPP-32 events / regulation of cardiac muscle contraction / regulation of cardiac conduction / regulation of macroautophagy / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / postsynaptic modulation of chemical synaptic transmission / renal water homeostasis / Hedgehog 'off' state / Ion homeostasis / regulation of proteasomal protein catabolic process / negative regulation of TORC1 signaling / regulation of G2/M transition of mitotic cell cycle / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / sperm midpiece / Recruitment of mitotic centrosome proteins and complexes / cellular response to epinephrine stimulus / calcium channel complex / negative regulation of smoothened signaling pathway / Mitochondrial protein degradation / Recruitment of NuMA to mitotic centrosomes / positive regulation of gluconeogenesis / Anchoring of the basal body to the plasma membrane / CD209 (DC-SIGN) signaling / cellular response to glucagon stimulus / protein serine/threonine/tyrosine kinase activity / positive regulation of calcium-mediated signaling / FCGR3A-mediated IL10 synthesis / regulation of heart rate / protein export from nucleus / AURKA Activation by TPX2 / acrosomal vesicle / positive regulation of protein export from nucleus / Regulation of insulin secretion / neural tube closure / Degradation of GLI1 by the proteasome / positive regulation of cholesterol biosynthetic process / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / cellular response to glucose stimulus / MAPK6/MAPK4 signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neuromuscular junction / positive regulation of insulin secretion / cytokine-mediated signaling pathway / VEGFA-VEGFR2 Pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / Regulation of PLK1 Activity at G2/M Transition / GPER1 signaling / manganese ion binding / Factors involved in megakaryocyte development and platelet production / cellular response to heat / peptidyl-serine phosphorylation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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. / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-L9L / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsHuang, X.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Azole-based inhibitors of AKT/PKB for the treatment of cancer.
Authors: Zeng, Q. / Allen, J.G. / Bourbeau, M.P. / Wang, X. / Yao, G. / Tadesse, S. / Rider, J.T. / Yuan, C.C. / Hong, F.T. / Lee, M.R. / Zhang, S. / Lofgren, J.A. / Freeman, D.J. / Yang, S. / Li, C. ...Authors: Zeng, Q. / Allen, J.G. / Bourbeau, M.P. / Wang, X. / Yao, G. / Tadesse, S. / Rider, J.T. / Yuan, C.C. / Hong, F.T. / Lee, M.R. / Zhang, S. / Lofgren, J.A. / Freeman, D.J. / Yang, S. / Li, C. / Tominey, E. / Huang, X. / Hoffman, D. / Yamane, H.K. / Fotsch, C. / Dominguez, C. / Hungate, R. / Zhang, X.
History
DepositionJan 5, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 16, 2011Group: Atomic model
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Nov 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
C: cAMP-dependent protein kinase inhibitor alpha
B: cAMP-dependent protein kinase catalytic subunit alpha
D: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,9356
Polymers86,0704
Non-polymers8652
Water13,565753
1
A: cAMP-dependent protein kinase catalytic subunit alpha
C: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4673
Polymers43,0352
Non-polymers4321
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-5 kcal/mol
Surface area16560 Å2
MethodPISA
2
B: cAMP-dependent protein kinase catalytic subunit alpha
D: cAMP-dependent protein kinase inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4673
Polymers43,0352
Non-polymers4321
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-4 kcal/mol
Surface area16440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.039, 114.424, 71.807
Angle α, β, γ (deg.)90.0, 125.786, 90.0
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-548-

HOH

21A-623-

HOH

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Components

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


Mass: 40808.570 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRKACA, PKACA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / cAMP-dependent protein kinase inhibitor / muscle/brain isoform / PKI-alpha


Mass: 2226.411 Da / Num. of mol.: 2 / Fragment: sequence database residues 6-25
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKIA, PRKACN1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61925
#3: Chemical ChemComp-L9L / 5-[2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propyl}amino)-1,3-thiazol-5-yl]-1,3-dihydro-2H-indol-2-one


Mass: 432.462 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H19F3N4OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 753 / Source method: isolated from a natural source / Formula: H2O
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: 2.29 Å3/Da / Density % sol: 46.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 1.0 M LiCl, 20-30% PEG6K, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. all: 60834 / Num. obs: 58036 / % possible obs: 95.4 % / Observed criterion σ(I): -3 / Redundancy: 2.45 % / Rmerge(I) obs: 0.047 / Net I/σ(I): 29.2
Reflection shellResolution: 1.9→1.97 Å / Rmerge(I) obs: 0.216 / Mean I/σ(I) obs: 5.53 / % possible all: 78.9

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Processing

Software
NameClassification
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1ATP

1atp


Resolution: 2→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.262 2580 RANDOM
Rwork0.219 --
all-52153 -
obs-50774 -
Refinement stepCycle: LAST / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5851 0 60 753 6664

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