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- PDB-8sf8: Structure of bovine PKA bound to (R)-N-(4-(1H-pyrrolo[2,3-b]pyrid... -

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Basic information

Entry
Database: PDB / ID: 8sf8
TitleStructure of bovine PKA bound to (R)-N-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2-amino-4-methylpentanamide
Components
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cAMP-dependent protein kinase inhibitor alpha
KeywordsCYTOSOLIC PROTEIN / Kinase / Type I kinase inhibitor / co-crystal structure
Function / homology
Function and homology information


CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Loss of Nlp from mitotic centrosomes ...CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / Factors involved in megakaryocyte development and platelet production / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / VEGFA-VEGFR2 Pathway / PKA activation / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cellular response to cold / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of osteoblast differentiation / sperm capacitation / Mitochondrial protein degradation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / protein kinase A regulatory subunit binding / mesoderm formation / sperm flagellum / plasma membrane raft / axoneme / postsynaptic modulation of chemical synaptic transmission / negative regulation of TORC1 signaling / regulation of proteasomal protein catabolic process / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / positive regulation of cholesterol biosynthetic process / cellular response to glucose stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neuromuscular junction / positive regulation of insulin secretion / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / peptidyl-serine phosphorylation / manganese ion binding / cellular response to heat / postsynapse / protein kinase activity / regulation of cell cycle / nuclear speck / protein phosphorylation / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / ubiquitin protein ligase binding / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / magnesium ion binding / signal transduction / 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. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...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. / 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
: / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsCoker, J.A. / Arya, T. / Goins, C.M. / Maw, J.J. / Macdonald, J.D. / Stauffer, S.R.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Characterization of Selective, First-in-Class Inhibitors of Citron Kinase.
Authors: Maw, J.J. / Coker, J.A. / Arya, T. / Goins, C.M. / Sonawane, D. / Han, S.H. / Rees, M.G. / Ronan, M.M. / Roth, J.A. / Wang, N.S. / Heemers, H.V. / Macdonald, J.D. / Stauffer, S.R.
History
DepositionApr 10, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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 inhibitor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6623
Polymers43,3392
Non-polymers3221
Water6,756375
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: Previously reported complex used for crystallization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2040 Å2
ΔGint-6 kcal/mol
Surface area16480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.653, 75.636, 80.652
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 41112.785 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: PRKACA / Production host: Escherichia coli (E. coli) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: Protein/peptide cAMP-dependent protein kinase inhibitor alpha / PKI-alpha


Mass: 2226.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Bos taurus (domestic cattle) / References: UniProt: Q3SX13
#3: Chemical ChemComp-ZWG / N-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-D-leucinamide


Mass: 322.404 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 375 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.56 Å3/Da / Density % sol: 51.89 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7
Details: 13 mg/mL PKA 1.25 uL + 1.25 uL 0.85 mM PKI(5-24) 25 mM Bis-Tris pH = 7.0 150 mM KCl 1.5 mM N-octanoyl N-methylglucamide (ONMG)

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Jun 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.7→55.17 Å / Num. obs: 49602 / % possible obs: 96.1 % / Redundancy: 12.5 % / Biso Wilson estimate: 28.22 Å2 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.043 / Net I/σ(I): 15.15
Reflection shellResolution: 1.7→1.76 Å / Rmerge(I) obs: 0.848 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 4887 / CC1/2: 0.251 / Rpim(I) all: 0.257 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia20.6.475-g7ac7bb6b-dials-2.2data reduction
DIALS2.2.10-g6dafd9427-releasedata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→55.17 Å / SU ML: 0.2232 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.8106
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2198 2403 4.85 %
Rwork0.1981 47111 -
obs0.1992 49514 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.62 Å2
Refinement stepCycle: LAST / Resolution: 1.7→55.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2944 0 24 375 3343
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01333091
X-RAY DIFFRACTIONf_angle_d1.434187
X-RAY DIFFRACTIONf_chiral_restr0.0707436
X-RAY DIFFRACTIONf_plane_restr0.014537
X-RAY DIFFRACTIONf_dihedral_angle_d8.2877413
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.730.35481360.32552730X-RAY DIFFRACTION99.79
1.73-1.770.32181570.30182712X-RAY DIFFRACTION99.97
1.77-1.810.32751480.272727X-RAY DIFFRACTION99.83
1.81-1.860.24151450.25312712X-RAY DIFFRACTION99.9
1.86-1.910.26171350.25142770X-RAY DIFFRACTION99.83
1.91-1.970.36011390.31862738X-RAY DIFFRACTION99.93
1.97-2.030.25471170.23012767X-RAY DIFFRACTION100
2.03-2.10.22311250.20752768X-RAY DIFFRACTION100
2.1-2.190.25561190.20092763X-RAY DIFFRACTION100
2.19-2.290.29281400.22082772X-RAY DIFFRACTION99.73
2.29-2.410.22251560.20232741X-RAY DIFFRACTION99.97
2.41-2.560.22451610.19172738X-RAY DIFFRACTION99.97
2.56-2.750.25111260.20012794X-RAY DIFFRACTION100
2.75-3.030.21841560.19542785X-RAY DIFFRACTION100
3.03-3.470.20841640.18732791X-RAY DIFFRACTION100
3.47-4.370.17961230.16332855X-RAY DIFFRACTION99.93
4.37-55.170.17081560.17462948X-RAY DIFFRACTION99.26

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