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- PDB-7y1g: Crystal structure of human PRKACA complexed with DS01080522 -

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Basic information

Entry
Database: PDB / ID: 7y1g
TitleCrystal structure of human PRKACA complexed with DS01080522
ComponentscAMP-dependent protein kinase catalytic subunit alpha
KeywordsTRANSFERASE / SERINE/THREONINE PROTEIN KINASE / protein kinase inhibitor
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 / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly / Rap1 signalling ...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 / 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 / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / sperm capacitation / PKA activation / 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 / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / 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 / Mitochondrial protein degradation / Recruitment of NuMA to mitotic centrosomes / protein kinase A signaling / calcium channel complex / Anchoring of the basal body to the plasma membrane / cellular response to epinephrine stimulus / regulation of cytosolic calcium ion concentration / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / VEGFA-VEGFR2 Pathway / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / Regulation of PLK1 Activity at G2/M Transition / cellular response to heat / Factors involved in megakaryocyte development and platelet production / manganese ion binding / peptidyl-serine phosphorylation / dendritic spine / regulation of cell cycle / protein kinase activity / nuclear speck / mitochondrial matrix / protein domain specific binding / protein phosphorylation
Similarity search - Function
cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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. ...cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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
Similarity search - Domain/homology
Chem-I5G / cAMP-dependent protein kinase catalytic subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsSuzuki, M. / Ubukata, O. / Toyoda, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Biochem.Biophys.Res.Commun. / Year: 2022
Title: Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model.
Authors: Toyota, A. / Goto, M. / Miyamoto, M. / Nagashima, Y. / Iwasaki, S. / Komatsu, T. / Momose, T. / Yoshida, K. / Tsukada, T. / Matsufuji, T. / Ohno, A. / Suzuki, M. / Ubukata, O. / Kaneta, Y.
History
DepositionJun 8, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
B: cAMP-dependent protein kinase catalytic subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,6255
Polymers81,6172
Non-polymers1,0083
Water4,594255
1
A: cAMP-dependent protein kinase catalytic subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2802
Polymers40,8091
Non-polymers4711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15530 Å2
MethodPISA
2
B: cAMP-dependent protein kinase catalytic subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,3453
Polymers40,8091
Non-polymers5372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-27 kcal/mol
Surface area15620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.221, 87.630, 113.476
Angle α, β, γ (deg.)90.000, 106.720, 90.000
Int Tables number5
Space group name H-MC121

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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: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P17612, cAMP-dependent protein kinase
#2: Chemical ChemComp-I5G / 1-chloranyl-~{N}-[(~{S})-(3-chloranyl-4-cyano-phenyl)-[(2~{R},4~{S})-4-oxidanylpyrrolidin-2-yl]methyl]-7-methoxy-isoquinoline-6-carboxamide


Mass: 471.336 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H20Cl2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.69 Å3/Da / Density % sol: 54.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.4
Details: 25 mM Tris, pH 8.4/ 20% PEG3350/ 0.05 M Zn Acetate/ 25 mM Glycine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Jun 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→45.76 Å / Num. obs: 37695 / % possible obs: 98 % / Redundancy: 3.7 % / CC1/2: 0.993 / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.062 / Rrim(I) all: 0.121 / Net I/σ(I): 5.5 / Num. measured all: 140987 / Scaling rejects: 7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.383.80.8331385936570.640.4920.9680.997.2
8.91-45.763.40.02922276530.9810.0190.03516.494.5

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Processing

Software
NameVersionClassification
Aimless0.7.7data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house structure of same protein

Resolution: 2.3→25 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.928 / SU B: 9.048 / SU ML: 0.199 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.296 / ESU R Free: 0.225 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2369 1892 5 %RANDOM
Rwork0.1855 ---
obs0.1881 35784 97.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 133.99 Å2 / Biso mean: 35.917 Å2 / Biso min: 13.71 Å2
Baniso -1Baniso -2Baniso -3
1-1.51 Å2-0 Å2-1.55 Å2
2---0.04 Å2-0 Å2
3----0.46 Å2
Refinement stepCycle: final / Resolution: 2.3→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5410 0 65 255 5730
Biso mean--33.85 36.69 -
Num. residues----673
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0125679
X-RAY DIFFRACTIONr_angle_refined_deg1.5561.6527708
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8385677
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.03822.297296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.91115929
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2051530
X-RAY DIFFRACTIONr_chiral_restr0.1120.2715
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024358
LS refinement shellResolution: 2.3→2.38 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.33 186 -
Rwork0.32 3449 -
all-3635 -
obs--96.96 %

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