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- PDB-6bfa: Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK... -

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Basic information

Entry
Database: PDB / ID: 6bfa
TitleCalcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553
ComponentsCalmodulin-domain protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / bumped kinase inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


protein kinase activity / phosphorylation / protein serine/threonine kinase activity / calcium ion binding / ATP binding / membrane / cytoplasm
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 / Phosphorylase Kinase; 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-UW5 / CAM kinase, CDPK family TgCDPK1 / Calmodulin-domain protein kinase 1
Similarity search - Component
Biological speciesToxoplasma gondii (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsMerritt, E.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI089441 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: 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
DepositionOct 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)55,6162
Polymers55,2271
Non-polymers3891
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area22350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.124, 72.655, 65.746
Angle α, β, γ (deg.)90.00, 99.78, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Calmodulin-domain protein kinase 1 / TgCDPK1


Mass: 55226.914 Da / Num. of mol.: 1 / Fragment: UNP residues 30-507
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Toxoplasma gondii (eukaryote) / Gene: CDPK1 / Plasmid: AVA0421 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9BJF5, UniProt: A0A0F7UUA6*PLUS, Ca2+/calmodulin-dependent protein kinase
#2: Chemical ChemComp-UW5 / 1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol / UW1553


Mass: 389.450 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.05 Å3/Da / Density % sol: 40.03 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 24% PEG3350, 0.275 M ammonium citrate, 5 mM DTT, 2 mM UW1533

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97944 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 11, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97944 Å / Relative weight: 1
ReflectionResolution: 2.8→36.23 Å / Num. obs: 10998 / % possible obs: 99 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.296 / Net I/σ(I): 5.8
Reflection shellResolution: 2.8→2.97 Å / Redundancy: 6.7 % / Rmerge(I) obs: 2.325 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMACREFMAC_5.8.0158refinement
Aimless0.1.29data scaling
PDB_EXTRACT3.22data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE MODEL

Resolution: 2.8→36.23 Å / SU B: 48.32 / SU ML: 0.434 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0 / ESU R Free: 0.478 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.253 475 4.8 %RANDOM
Rwork0.199 ---
obs0.201 9459 89.4 %-
Displacement parametersBiso mean: 69.6 Å2
Baniso -1Baniso -2Baniso -3
1--2.5 Å20 Å2-1.15 Å2
2---0.76 Å20 Å2
3---3.45 Å2
Refinement stepCycle: LAST / Resolution: 2.8→36.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3708 0 29 87 3824
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)
14.45012.7537-0.16246.6331.83042.4499-0.2737-0.27330.2825-0.8094-0.0820.6271-0.4324-0.17470.35570.13840.0106-0.13340.06990.00850.15743.641-21.474-40.056
20.95760.4704-0.84110.9005-0.0673.77460.0523-0.0551-0.128-0.0217-0.19430.06340.0659-0.21010.1420.03920.0002-0.09240.1169-0.01570.25273.907-24.002-24.592
32.64020.4509-0.32343.1571-0.1071.55910.0067-0.11280.04060.3327-0.1377-0.14560.1341-0.15890.1310.0904-0.023-0.07240.1914-0.00660.13337.737-16.1-8.377
412.82793.23499.19210.8262.31376.59131.12130.0507-1.34280.3163-0.0828-0.31270.80350.0451-1.03840.46750.03150.17120.44410.03080.5105-2.627-36.8330.06
50.7081-0.5040.81380.6985-1.53135.201-0.067-0.14130.1577-0.21530.0589-0.03170.5498-0.42850.00810.2807-0.0321-0.11670.2423-0.04330.2525-11.544-7.431-36.719
69.9117-2.11773.46682.37661.33777.54440.49170.1302-0.3131-0.5013-0.034-0.1099-0.17740.5255-0.45770.3815-0.0694-0.16860.13380.02910.1735-15.075-11.396-51.475
74.60031.5493-2.28971.3078-1.75093.27620.0162-0.10810.2729-0.02550.21520.0258-0.0539-0.1496-0.23140.0603-0.0107-0.08430.1609-0.09040.2756-16.754-0.753-22.871
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A44 - 99
2X-RAY DIFFRACTION2A100 - 211
3X-RAY DIFFRACTION3A212 - 313
4X-RAY DIFFRACTION4A314 - 320
5X-RAY DIFFRACTION5A321 - 383
6X-RAY DIFFRACTION6A384 - 432
7X-RAY DIFFRACTION7A433 - 507

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