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- PDB-4tzr: Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK... -

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Basic information

Entry
Database: PDB / ID: 4tzr
TitleCalcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1561
ComponentsCalmodulin-domain protein kinase 1
KeywordsTRANSFERASE / serine/threonine protein kinase / calcium-binding / ATP-binding / bumped kinase inhibitor
Function / homology
Function and homology information


protein serine/threonine kinase activity / calcium ion binding / ATP binding / membrane
Similarity search - Function
: / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...: / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / 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
Chem-UW2 / Calmodulin-domain protein kinase 1
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsMerritt, E.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI089441 United States
Citation
Journal: J. Med. Chem. / Year: 2016
Title: Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related ...Title: Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.
Authors: Vidadala, R.S. / Rivas, K.L. / Ojo, K.K. / Hulverson, M.A. / Zambriski, J.A. / Bruzual, I. / Schultz, T.L. / Huang, W. / Zhang, Z. / Scheele, S. / DeRocher, A.E. / Choi, R. / Barrett, L.K. / ...Authors: Vidadala, R.S. / Rivas, K.L. / Ojo, K.K. / Hulverson, M.A. / Zambriski, J.A. / Bruzual, I. / Schultz, T.L. / Huang, W. / Zhang, Z. / Scheele, S. / DeRocher, A.E. / Choi, R. / Barrett, L.K. / Siddaramaiah, L.K. / Hol, W.G. / Fan, E. / Merritt, E.A. / Parsons, M. / Freiberg, G. / Marsh, K. / Kempf, D.J. / Carruthers, V.B. / Isoherranen, N. / Doggett, J.S. / Van Voorhis, W.C. / Maly, D.J.
#1: Journal: Nat.Struct.Mol.Biol. / Year: 2010
Title: Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.
Authors: Ojo, K.K. / Larson, E.T. / Keyloun, K.R. / Castaneda, L.J. / Derocher, A.E. / Inampudi, K.K. / Kim, J.E. / Arakaki, T.L. / Murphy, R.C. / Zhang, L. / Napuli, A.J. / Maly, D.J. / Verlinde, C. ...Authors: Ojo, K.K. / Larson, E.T. / Keyloun, K.R. / Castaneda, L.J. / Derocher, A.E. / Inampudi, K.K. / Kim, J.E. / Arakaki, T.L. / Murphy, R.C. / Zhang, L. / Napuli, A.J. / Maly, D.J. / Verlinde, C.L. / Buckner, F.S. / Parsons, M. / Hol, W.G. / Merritt, E.A. / Van Voorhis, W.C.
#2: Journal: J.Med.Chem. / Year: 2012
Title: Multiple determinants for selective inhibition of apicomplexan calcium-dependent protein kinase CDPK1.
Authors: Larson, E.T. / Ojo, K.K. / Murphy, R.C. / Johnson, S.M. / Zhang, Z. / Kim, J.E. / Leibly, D.J. / Fox, A.M. / Reid, M.C. / Dale, E.J. / Perera, B.G. / Kim, J. / Hewitt, S.N. / Hol, W.G. / ...Authors: Larson, E.T. / Ojo, K.K. / Murphy, R.C. / Johnson, S.M. / Zhang, Z. / Kim, J.E. / Leibly, D.J. / Fox, A.M. / Reid, M.C. / Dale, E.J. / Perera, B.G. / Kim, J. / Hewitt, S.N. / Hol, W.G. / Verlinde, C.L. / Fan, E. / Van Voorhis, W.C. / Maly, D.J. / Merritt, E.A.
History
DepositionJul 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 27, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Derived calculations / Other / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.2Nov 8, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Calmodulin-domain protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6172
Polymers55,2271
Non-polymers3901
Water2,306128
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area22680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.240, 73.090, 66.240
Angle α, β, γ (deg.)90.000, 100.380, 90.000
Int Tables number4
Space group name H-MP1211
Detailsbiological unit is the same as AU

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Components

#1: Protein Calmodulin-domain protein kinase 1


Mass: 55226.914 Da / Num. of mol.: 1 / Fragment: UNP residues 30-507 / Mutation: N-term 29 residues replaced with His tag
Source method: isolated from a genetically manipulated source
Details: residues 1-29 were replaced with a cleavable His-tag plus linker during cloning; tag was cleaved prior to crystallization
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: CDPK1 / Plasmid: AVA0421 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9BJF5
#2: Chemical ChemComp-UW2 / 1-{4-amino-3-[2-(cyclopropyloxy)quinolin-6-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol


Mass: 390.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O

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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: 2.08 Å3/Da / Density % sol: 40.86 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 28% PEG 3350, 250 mM ammonium citrate, 2 mM EDTA, 5 mM DTT, 2 mM UW1561

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jan 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2→48.64 Å / Num. obs: 30683 / % possible obs: 99.9 % / Redundancy: 7.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.152 / Rpim(I) all: 0.06 / Net I/σ(I): 9.6 / Num. measured all: 226046 / Scaling rejects: 53
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2-2.057.22.2470.91622222480.1020.89699.1
8.94-48.6470.03143.625883700.9990.01399.4

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Processing

Software
NameVersionClassification
Aimless0.1.26data scaling
REFMACrefinement
PDB_EXTRACT3.14data extraction
REFMAC5.8.0049refinement
RefinementResolution: 2→48.64 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.943 / WRfactor Rfree: 0.2175 / WRfactor Rwork: 0.1847 / FOM work R set: 0.7438 / SU B: 14.94 / SU ML: 0.188 / SU R Cruickshank DPI: 0.2268 / SU Rfree: 0.18 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.227 / ESU R Free: 0.18 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2416 1499 4.9 %RANDOM
Rwork0.2072 29165 --
obs0.2089 30664 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 141.41 Å2 / Biso mean: 50.165 Å2 / Biso min: 20.73 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å2-0 Å2-0.23 Å2
2---0.37 Å2-0 Å2
3---0.5 Å2
Refinement stepCycle: final / Resolution: 2→48.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3691 0 34 128 3853
Biso mean--36.94 43.21 -
Num. residues----461
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0193860
X-RAY DIFFRACTIONr_bond_other_d0.0010.023720
X-RAY DIFFRACTIONr_angle_refined_deg1.5671.9685212
X-RAY DIFFRACTIONr_angle_other_deg0.80138597
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8295481
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.30224.783184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.35915745
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8491523
X-RAY DIFFRACTIONr_chiral_restr0.0920.2574
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024456
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02859
X-RAY DIFFRACTIONr_mcbond_it3.2393.8171865
X-RAY DIFFRACTIONr_mcbond_other3.2273.8151863
X-RAY DIFFRACTIONr_mcangle_it5.0315.7072332
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 100 -
Rwork0.38 2143 -
all-2243 -
obs--99.12 %
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)
11.03570.54190.51381.06770.64791.9326-0.1765-0.02750.0443-0.40770.03190.1434-0.3756-0.15090.14460.16950.0021-0.06590.0879-0.0050.06772.8032-20.0707-41.0677
20.17090.1658-0.09660.53520.58631.3082-0.0224-0.0381-0.0342-0.0272-0.08770.03420.0333-0.06950.11010.0215-0.0002-0.03220.13120.00460.10655.0938-22.0797-25.5178
30.1727-0.02820.29040.6327-0.13840.5139-0.0057-0.06660.02170.065-0.0227-0.0249-0.0005-0.09050.02840.0144-0.0104-0.00960.18350.00670.05431.8934-11.7327-16.0511
43.99222.52910.72912.75610.71920.19230.14570.0459-0.25070.1073-0.13340.05880.0462-0.0249-0.01220.15330.0082-0.07980.0464-0.03240.0927-14.5528-9.2087-52.2374
53.51281.4708-1.85090.8241-0.63362.63750.0539-0.04890.177-0.02580.13610.0127-0.117-0.1136-0.190.0278-0.0214-0.01450.1495-0.04630.1035-16.59371.4232-21.9749
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 94
2X-RAY DIFFRACTION2A95 - 214
3X-RAY DIFFRACTION3A215 - 373
4X-RAY DIFFRACTION4A374 - 435
5X-RAY DIFFRACTION5A436 - 507

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