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- PDB-4c36: PKA-S6K1 Chimera with compound 15e (CCT147581) bound -

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Basic information

Entry
Database: PDB / ID: 4c36
TitlePKA-S6K1 Chimera with compound 15e (CCT147581) bound
Components
  • CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
  • CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX / CHIMERA / S6K1
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 / Factors involved in megakaryocyte development and platelet production ...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 / Factors involved in megakaryocyte development and platelet production / 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 / RET signaling / AURKA Activation by TPX2 / 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 / cellular response to cold / Mitochondrial protein degradation / sperm capacitation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / protein kinase A regulatory subunit binding / intracellular potassium ion homeostasis / mesoderm formation / plasma membrane raft / axoneme / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of proteasomal protein catabolic process / negative regulation of TORC1 signaling / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / acrosomal vesicle / protein export from nucleus / positive regulation of phagocytosis / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / neuromuscular junction / cellular response to glucose stimulus / positive regulation of cholesterol biosynthetic process / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / peptidyl-serine phosphorylation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / mRNA processing / manganese ion binding / cellular response to heat / protein phosphorylation / protein kinase activity / postsynapse / regulation of cell cycle / nuclear speck / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / centrosome / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / magnesium ion binding / signal transduction / mitochondrion / ATP binding / nucleus / cytoplasm / cytosol
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
METHANOL / Chem-ZO9 / 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: 1.98 Å
AuthorsCouty, S. / Westwood, I.M. / Kalusa, A. / Cano, C. / Travers, J. / Boxall, K. / Chow, C.L. / Burns, S. / Schmitt, J. / Pickard, L. ...Couty, S. / Westwood, I.M. / Kalusa, A. / Cano, C. / Travers, J. / Boxall, K. / Chow, C.L. / Burns, S. / Schmitt, J. / Pickard, L. / Barillari, C. / McAndrew, P.C. / Clarke, P.A. / Linardopoulos, S. / Griffin, R.J. / Aherne, G.W. / Raynaud, F.I. / Workman, P. / Jones, K. / van Montfort, R.L.M.
CitationJournal: Oncotarget / Year: 2013
Title: The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.
Authors: Couty, S. / Westwood, I.M. / Kalusa, A. / Cano, C. / Travers, J. / Boxall, K. / Chow, C.L. / Burns, S. / Schmitt, J. / Pickard, L. / Barillari, C. / McAndrew, P.C. / Clarke, P.A. / ...Authors: Couty, S. / Westwood, I.M. / Kalusa, A. / Cano, C. / Travers, J. / Boxall, K. / Chow, C.L. / Burns, S. / Schmitt, J. / Pickard, L. / Barillari, C. / McAndrew, P.C. / Clarke, P.A. / Linardopoulos, S. / Griffin, R.J. / Aherne, G.W. / Raynaud, F.I. / Workman, P. / Jones, K. / van Montfort, R.L.
History
DepositionAug 21, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 9, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2013Group: Database references
Revision 1.2Oct 9, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: citation / citation_author ...citation / citation_author / pdbx_database_status / struct_conn
Item: _citation.page_last / _citation.pdbx_database_id_DOI ..._citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Dec 20, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 16, 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

Downloads & links

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Assembly

Deposited unit
A: CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA
I: CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,5424
Polymers43,2552
Non-polymers2872
Water6,792377
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2030 Å2
ΔGint-4.3 kcal/mol
Surface area15830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.560, 75.850, 80.380
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: 41028.641 Da / Num. of mol.: 1 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: PKA-S6K1 CHIMERA / Source: (gene. exp.) BOS TAURUS (domestic cattle) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / 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 / Fragment: RESIDUES 6-25 / Source method: obtained synthetically / Source: (synth.) BOS TAURUS (domestic cattle) / References: UniProt: Q3SX13
#3: Chemical ChemComp-ZO9 / 4-[1-(cyclopropylmethyl)-1H-benzimidazol-2-yl]-1,2,5-oxadiazol-3-amine


Mass: 255.275 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13N5O
#4: Chemical ChemComp-MOH / METHANOL


Mass: 32.042 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH4O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 377 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Sequence detailsPKA-S6K1 CHIMERA MUTATIONS ARE F54Y, M120L, V123L, L173M AND Q181K

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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: 52.25 % / Description: NONE
Crystal growpH: 6.4
Details: 18 MG/ML PROTEIN IN 25MM MES-BIS-TRIS PH 6.5, 75MM LICL, 0.1MM EDTA, 1MM MEGA-8, 1MM DTT AND 1MM PKI PEPTIDE MIXED 1:1 WITH 8-16% AQUEOUS METHANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9795
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.98→55.17 Å / Num. obs: 31577 / % possible obs: 99.8 % / Observed criterion σ(I): 1.5 / Redundancy: 3.9 % / Biso Wilson estimate: 27.22 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.5
Reflection shellResolution: 1.98→2.03 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 3.3 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4C33

4c33


Resolution: 1.98→55.17 Å / Cor.coef. Fo:Fc: 0.9559 / Cor.coef. Fo:Fc free: 0.936 / SU R Cruickshank DPI: 0.133 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.145 / SU Rfree Blow DPI: 0.127 / SU Rfree Cruickshank DPI: 0.123
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.1901 1582 5.04 %RANDOM
Rwork0.1567 ---
obs0.1584 31409 99.56 %-
Displacement parametersBiso mean: 30.2 Å2
Baniso -1Baniso -2Baniso -3
1--1.9296 Å20 Å20 Å2
2---3.4511 Å20 Å2
3---5.3807 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: LAST / Resolution: 1.98→55.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2883 0 21 377 3281
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013043HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.944135HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1040SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes468HARMONIC5
X-RAY DIFFRACTIONt_it3043HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion15.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion384SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3812SEMIHARMONIC4
LS refinement shellResolution: 1.98→2.04 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2527 133 4.67 %
Rwork0.1844 2713 -
all0.1874 2846 -
obs--99.56 %
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)
11.4028-0.7463-0.40295.8704-1.64971.7298-0.0049-0.07370.1750.54050.24650.4532-0.4141-0.9114-0.24170.15570.09760.10420.28450.01190.159-39.2806-1.266318.5383
22.73930.0118-0.74411.81420.21394.88440.04040.1336-0.1502-0.19570.00840.05390.4079-0.1332-0.04890.1335-0.0662-0.01420.1409-0.04020.1698-33.4323-20.2475-1.7202
30.77540.2785-0.05420.9966-0.52921.7234-0.01020.0639-0.0117-0.03370.04590.1287-0.0759-0.2053-0.03570.05880.0104-0.00030.0912-0.03120.0758-29.2033-5.14162.1535
40.58740.2607-0.02710.8487-0.80381.61670.0325-0.00980.09850.0674-0.10970.0028-0.2660.13690.07720.1624-0.0042-0.00370.1103-0.0120.0964-17.54614.19724.3026
52.29970.05780.22461.6055-0.6052.56280.0065-0.03420.41660.1250.0380.1485-0.7077-0.1919-0.04450.27630.0870.02150.026-0.02020.1417-28.884915.56011.3071
61.53750.30721.23111.8022-0.43114.185-0.00030.2101-0.1822-0.20930.005-0.13820.44550.1483-0.00470.0931-0.02710.06670.0926-0.03040.1-26.2858-20.2652-2.1521
71.7565-0.1655-1.23731.7646-2.83574.2110.08920.09360.04770.0092-0.080.13810.01150.067-0.00920.1882-0.02410.00210.20380.00210.0949-13.10065.139-14.2918
82.405-0.1179-0.38311.03810.68481.2502-0.13240.0237-0.54760.1511-0.0364-0.21610.6527-0.1250.16890.27490.0179-0.00380.14830.02740.148-16.0939-5.4038-1.5173
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|15 - A|34 }
2X-RAY DIFFRACTION2{ A|35 - A|72 }
3X-RAY DIFFRACTION3{ A|73 - A|180 }
4X-RAY DIFFRACTION4{ A|181 - A|254 }
5X-RAY DIFFRACTION5{ A|255 - A|317 }
6X-RAY DIFFRACTION6{ A|318 - A|350 }
7X-RAY DIFFRACTION7{ I|5 - I|17 }
8X-RAY DIFFRACTION8{ I|18 - I|23 }

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