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- PDB-4c35: PKA-S6K1 Chimera with compound 1 (NU1085) bound -

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Basic information

Entry
Database: PDB / ID: 4c35
TitlePKA-S6K1 Chimera with compound 1 (NU1085) 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
Chem-NU3 / 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: 2.19 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 1.4Nov 20, 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)43,3734
Polymers43,0022
Non-polymers3712
Water3,207178
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-18.2 kcal/mol
Surface area16100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.440, 73.380, 77.340
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: 1973.177 Da / Num. of mol.: 1 / Fragment: RESIDUES 6-23 / Source method: obtained synthetically / Source: (synth.) BOS TAURUS (domestic cattle) / References: UniProt: Q3SX13
#3: Chemical ChemComp-NU3 / 2-(4-hydroxyphenyl)-1H-benzimidazole-4-carboxamide


Mass: 253.256 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11N3O2
#4: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 178 / 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: 2.5 Å3/Da / Density % sol: 51.2 % / 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: Diamond / Beamline: I02 / Wavelength: 0.9795
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 7, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.19→53.23 Å / Num. obs: 21188 / % possible obs: 99.6 % / Observed criterion σ(I): 1.5 / Redundancy: 3.9 % / Biso Wilson estimate: 40.67 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 15.6
Reflection shellResolution: 2.19→2.26 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 3.9 / % possible all: 99.7

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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: 2.19→53.23 Å / Cor.coef. Fo:Fc: 0.9493 / Cor.coef. Fo:Fc free: 0.9217 / SU R Cruickshank DPI: 0.239 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.253 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.202
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 1072 5.07 %RANDOM
Rwork0.1829 ---
obs0.1857 21129 99.42 %-
Displacement parametersBiso mean: 43.67 Å2
Baniso -1Baniso -2Baniso -3
1--4.0672 Å20 Å20 Å2
2--0.6744 Å20 Å2
3---3.3928 Å2
Refine analyzeLuzzati coordinate error obs: 0.285 Å
Refinement stepCycle: LAST / Resolution: 2.19→53.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2890 0 27 178 3095
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013002HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.024076HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1008SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes456HARMONIC5
X-RAY DIFFRACTIONt_it3002HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion17.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion376SEMIHARMONIC5
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_contact3619SEMIHARMONIC4
LS refinement shellResolution: 2.19→2.3 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2656 146 5.25 %
Rwork0.1993 2633 -
all0.2029 2779 -
obs--99.42 %
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)
11.36890.2278-0.47772.44230.09521.9996-0.01790.01360.00140.0853-0.03420.1259-0.02060.06030.0521-0.20770.03740.0075-0.1674-0.0154-0.12579.88690.821493.4719
22.61550.46661.89570.00790.9291.9590.059-0.0679-0.3043-0.0042-0.05050.23380.0954-0.4209-0.0085-0.1192-0.03630.0691-0.1514-0.04970.175-5.006480.0822100.502
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN I

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