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- PDB-3e8e: Crystal structures of the kinase domain of PKA in complex with AT... -

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Basic information

Entry
Database: PDB / ID: 3e8e
TitleCrystal structures of the kinase domain of PKA in complex with ATP-competitive inhibitors
Components
  • PKI inhibitor peptide
  • cAMP-dependent protein kinase catalytic subunit alpha
KeywordsTRANSFERASE / PKA / AKT2 / kinase / PKI / bovine / inhibitor / ATP-binding / cAMP / Lipoprotein / Myristate / Nucleotide-binding / Nucleus / Phosphoprotein / Serine/threonine-protein kinase
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 / regulation of osteoblast differentiation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to cold / 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 / cellular response to glucose stimulus / positive regulation of cholesterol biosynthetic process / 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. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-G98 / 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 / Resolution: 2 Å
AuthorsConcha, N.O. / Elkins, P.A. / Smallwood, A. / Ward, P.
Citation
#1: Journal: To be Published
Title: Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors
Authors: Seefeld, M.A. / Rouse, M.B. / McNulty, K.C. / Sun, L. / Wang, J. / Yamashita, D.S. / Choudhry, A. / Schaber, M.D. / Kumar, R. / Kahana, J. / Zhang, S.Y. / Minthorn, E.A. / Koretke, K.K. / ...Authors: Seefeld, M.A. / Rouse, M.B. / McNulty, K.C. / Sun, L. / Wang, J. / Yamashita, D.S. / Choudhry, A. / Schaber, M.D. / Kumar, R. / Kahana, J. / Zhang, S.Y. / Minthorn, E.A. / Koretke, K.K. / Concha, N.O. / Heerding, D.A.
History
DepositionAug 19, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 18, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 19, 2014Group: Non-polymer description
Revision 1.3Oct 25, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.4Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
G: PKI inhibitor peptide
B: cAMP-dependent protein kinase catalytic subunit alpha
C: PKI inhibitor peptide
E: cAMP-dependent protein kinase catalytic subunit alpha
F: PKI inhibitor peptide
I: cAMP-dependent protein kinase catalytic subunit alpha
J: PKI inhibitor peptide
L: cAMP-dependent protein kinase catalytic subunit alpha
N: PKI inhibitor peptide
P: cAMP-dependent protein kinase catalytic subunit alpha
Q: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)260,85818
Polymers258,07712
Non-polymers2,7816
Water6,053336
1
A: cAMP-dependent protein kinase catalytic subunit alpha
G: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2120 Å2
ΔGint-5 kcal/mol
Surface area16890 Å2
MethodPISA
2
B: cAMP-dependent protein kinase catalytic subunit alpha
C: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2110 Å2
ΔGint-1 kcal/mol
Surface area16350 Å2
MethodPISA
3
E: cAMP-dependent protein kinase catalytic subunit alpha
F: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-5 kcal/mol
Surface area17070 Å2
MethodPISA
4
I: cAMP-dependent protein kinase catalytic subunit alpha
J: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-3 kcal/mol
Surface area17000 Å2
MethodPISA
5
L: cAMP-dependent protein kinase catalytic subunit alpha
N: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-2 kcal/mol
Surface area16480 Å2
MethodPISA
6
P: cAMP-dependent protein kinase catalytic subunit alpha
Q: PKI inhibitor peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,4763
Polymers43,0132
Non-polymers4641
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2130 Å2
ΔGint-3 kcal/mol
Surface area16670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.578, 95.848, 179.097
Angle α, β, γ (deg.)90.00, 102.53, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31E
41I
51L
61P
12G
22C
32F
42J
52N
62Q

NCS domain segments:

Component-ID: 1 / Refine code: 5

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUPHEPHEAA17 - 35017 - 350
21GLUGLUPHEPHEBC17 - 35017 - 350
31GLUGLUPHEPHEEE17 - 35017 - 350
41GLUGLUPHEPHEIG17 - 35017 - 350
51GLUGLUPHEPHELI17 - 35017 - 350
61GLUGLUPHEPHEPK17 - 35017 - 350
12TYRTYRHISHISGB7 - 233 - 19
22TYRTYRHISHISCD7 - 233 - 19
32TYRTYRHISHISFF7 - 233 - 19
42TYRTYRHISHISJH7 - 233 - 19
52TYRTYRHISHISNJ7 - 233 - 19
62TYRTYRHISHISQL7 - 233 - 19

NCS ensembles :
ID
1
2

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Components

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


Mass: 40786.395 Da / Num. of mol.: 6 / Fragment: CAMP-DEPENDENT PKA kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: PKA, PRKACA / Plasmid: pDEST14 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(AI) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: Protein/peptide
PKI inhibitor peptide


Mass: 2226.411 Da / Num. of mol.: 6 / Source method: obtained synthetically
Details: THE PEPTIDE WAS CHEMICALLY SYNTHESIZED. IT IS FOUND NATURALLY IN BOVINE.
References: UniProt: Q3SX13
#3: Chemical
ChemComp-G98 / 4-[2-(4-amino-2,5-dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol


Mass: 463.532 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C24H29N7O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 336 / 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: 2.68 Å3/Da / Density % sol: 54.12 %
Crystal growTemperature: 273 K / Method: vapor diffusion
Details: 13-17% PEG 3K-20K, 100 mM MES pH 6.5 or acetate 4.6, 1-15% methanol. Seeded, pH 4.5 - 6.5, vapor diffusion, temperature 273K
PH range: 4.5 - 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 1, 2005 / Details: un-focused beam
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.72→42.03 Å / Num. obs: 211201 / % possible obs: 73.7 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Rmerge(I) obs: 0.09
Reflection shellResolution: 1.72→1.78 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.82 / % possible all: 17.3

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.006data extraction
JDirectordata collection
HKL-2000data reduction
AMoREphasing
RefinementResolution: 2→42.03 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.919 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 8.838 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.23 / ESU R Free: 0.196 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2794 8636 5 %RANDOM
Rwork0.24311 ---
obs0.24492 163336 93.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.635 Å2
Baniso -1Baniso -2Baniso -3
1--2.55 Å20 Å2-1.53 Å2
2--3.37 Å20 Å2
3----1.48 Å2
Refinement stepCycle: LAST / Resolution: 2→42.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17910 0 204 336 18450
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.02218613
X-RAY DIFFRACTIONr_bond_other_d0.0010.0212911
X-RAY DIFFRACTIONr_angle_refined_deg1.2341.96725160
X-RAY DIFFRACTIONr_angle_other_deg0.795331296
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.42352179
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.97923.974926
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.35415.0463275
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.43115108
X-RAY DIFFRACTIONr_chiral_restr0.0620.22612
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0220434
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024002
X-RAY DIFFRACTIONr_nbd_refined0.190.23796
X-RAY DIFFRACTIONr_nbd_other0.1760.213029
X-RAY DIFFRACTIONr_nbtor_refined0.1790.29084
X-RAY DIFFRACTIONr_nbtor_other0.0820.29320
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1410.2668
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0380.21
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1760.213
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2880.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1630.29
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4541.511789
X-RAY DIFFRACTIONr_mcbond_other0.1121.54401
X-RAY DIFFRACTIONr_mcangle_it0.69217509
X-RAY DIFFRACTIONr_scbond_it0.90538743
X-RAY DIFFRACTIONr_scangle_it1.3344.57644
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A1970medium positional0.220.5
12B1970medium positional0.240.5
13E1970medium positional0.210.5
14I1970medium positional0.280.5
15L1970medium positional0.190.5
16P1970medium positional0.220.5
21G100medium positional0.140.5
22C100medium positional0.20.5
23F100medium positional0.240.5
24J100medium positional0.180.5
25N100medium positional0.330.5
26Q100medium positional0.440.5
11A2766loose positional0.45
12B2766loose positional0.435
13E2766loose positional0.515
14I2766loose positional0.665
15L2766loose positional0.475
16P2766loose positional0.425
21G133loose positional0.545
22C133loose positional0.665
23F133loose positional0.65
24J133loose positional0.445
25N133loose positional0.665
26Q133loose positional0.595
11A1970medium thermal0.422
12B1970medium thermal0.372
13E1970medium thermal0.542
14I1970medium thermal0.572
15L1970medium thermal0.682
16P1970medium thermal0.672
21G100medium thermal0.442
22C100medium thermal0.472
23F100medium thermal0.582
24J100medium thermal0.332
25N100medium thermal0.272
26Q100medium thermal0.692
11A2766loose thermal0.910
12B2766loose thermal0.8510
13E2766loose thermal1.0610
14I2766loose thermal1.0810
15L2766loose thermal1.1910
16P2766loose thermal1.2110
21G133loose thermal1.3110
22C133loose thermal1.1110
23F133loose thermal1.2410
24J133loose thermal1.2710
25N133loose thermal0.6910
26Q133loose thermal1.3410
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 463 -
Rwork0.318 9514 -
obs--73.57 %

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