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- PDB-3zo1: The Synthesis and Evaluation of Diazaspirocyclic Protein Kinase I... -

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Basic information

Entry
Database: PDB / ID: 3zo1
TitleThe Synthesis and Evaluation of Diazaspirocyclic Protein Kinase Inhibitors
Components(CAMP-DEPENDENT PROTEIN KINASE ...) x 2
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX
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 / cAMP-dependent protein kinase activity / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Mitochondrial protein degradation / protein kinase A regulatory subunit binding / mesoderm formation / sperm flagellum / negative regulation of TORC1 signaling / protein kinase A signaling / acrosomal vesicle / neuromuscular junction / cellular response to heat / peptidyl-serine phosphorylation / protein kinase activity / protein phosphorylation / protein domain specific binding / protein serine kinase activity / protein serine/threonine kinase activity / perinuclear region of cytoplasm / mitochondrion / ATP binding / nucleus / plasma membrane / 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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 / 6-(1,9-DIAZASPIRO[5.5]UNDECAN-9-YL)-9H-PURINE / cAMP-dependent protein kinase catalytic subunit alpha / cAMP-dependent protein kinase inhibitor alpha
Similarity search - Component
Biological speciesBOS TAURUS (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAllen, C.E. / Chow, C.L. / Caldwell, J.J. / Westwood, I.M. / van Montfort, R.L. / Collins, I.
CitationJournal: Bioorg. Med. Chem. / Year: 2013
Title: Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases.
Authors: Allen, C.E. / Chow, C.L. / Caldwell, J.J. / Westwood, I.M. / van Montfort, R.L. / Collins, I.
History
DepositionFeb 20, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2013Group: Database references
Revision 1.2Aug 28, 2013Group: Database references
Revision 1.3Mar 28, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.4Apr 3, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.temp / _struct_conn.pdbx_leaving_atom_flag
Revision 1.5Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)43,5969
Polymers42,8912
Non-polymers7057
Water7,170398
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3530 Å2
ΔGint-1.3 kcal/mol
Surface area16300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.940, 76.350, 80.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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CAMP-DEPENDENT PROTEIN KINASE ... , 2 types, 2 molecules AI

#1: Protein CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT ALPHA / PKA C-ALPHA


Mass: 40917.590 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (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 (cattle) / References: UniProt: Q3SX13

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Non-polymers , 4 types, 405 molecules

#3: Chemical ChemComp-SIJ / 6-(1,9-DIAZASPIRO[5.5]UNDECAN-9-YL)-9H-PURINE


Mass: 272.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-MOH / METHANOL


Mass: 32.042 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH4O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 398 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.74 Å3/Da / Density % sol: 55.07 % / Description: NONE
Crystal growTemperature: 277 K / pH: 6.5
Details: 25MM MES-BISTRIS PH6.5, 75MM LICL, 1MM DTT, 0.1MM EDTA, 1.5MM MEGA8; 4 DEGREE CELSIUS

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Data collection

DiffractionMean temperature: 287 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9763
DetectorType: ADSC CCD / Detector: CCD / Date: Aug 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2→55.42 Å / Num. obs: 31064 / % possible obs: 99.9 % / Observed criterion σ(I): 1.5 / Redundancy: 3.9 % / Biso Wilson estimate: 27.59 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 12
Reflection shellResolution: 2→2.05 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2.4 / % 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 2GFC

2gfc


Resolution: 2→55.42 Å / Cor.coef. Fo:Fc: 0.9549 / Cor.coef. Fo:Fc free: 0.9308 / SU R Cruickshank DPI: 0.14 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.153 / SU Rfree Blow DPI: 0.13 / SU Rfree Cruickshank DPI: 0.124
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.1895 1564 5.04 %RANDOM
Rwork0.16 ---
obs0.1616 31013 99.78 %-
Displacement parametersBiso mean: 30.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.631 Å20 Å20 Å2
2---3.2433 Å20 Å2
3---3.8743 Å2
Refinement stepCycle: LAST / Resolution: 2→55.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2891 0 48 398 3337
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013030HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.964102HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1044SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes453HARMONIC5
X-RAY DIFFRACTIONt_it3030HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.1
X-RAY DIFFRACTIONt_other_torsion17.11
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion378SEMIHARMONIC5
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_contact3843SEMIHARMONIC4
LS refinement shellResolution: 2→2.07 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2261 147 5.19 %
Rwork0.1934 2684 -
all0.1951 2831 -
obs--99.78 %
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)
10.89370.2188-0.03541.0222-0.38221.2725-0.01410.05550.0368-0.02870.03920.0895-0.0723-0.1194-0.0251-0.08940.00910.0025-0.0472-0.0191-0.1055-27.3651-1.96892.7837
21.23910.7946-1.31461.4507-1.45551.1126-0.04580.115-0.12940.0763-0.05680.03160.06070.06060.10260.0346-0.00630.02650.0089-0.01-0.0785-14.13891.7971-10.679
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A
2X-RAY DIFFRACTION2CHAIN I

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