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- PDB-8em8: Co-crystal structure of the cGMP-dependent protein kinase PKG fro... -

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Basic information

Entry
Database: PDB / ID: 8em8
TitleCo-crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium falciparum in complex with RY-1-165
Components
  • cGMP-dependent protein kinase
  • unidentified peptide fragment
KeywordsTRANSFERASE / SGC / cGMP-kinase / inhibitor / Structural Genomics / Structural Genomics Consortium
Function / homology
Function and homology information


cGMP-dependent protein kinase / cGMP-dependent protein kinase activity / gamete generation / cAMP-dependent protein kinase activity / cAMP-dependent protein kinase complex / extrinsic component of membrane / cGMP binding / protein kinase A signaling / protein phosphorylation / protein serine kinase activity ...cGMP-dependent protein kinase / cGMP-dependent protein kinase activity / gamete generation / cAMP-dependent protein kinase activity / cAMP-dependent protein kinase complex / extrinsic component of membrane / cGMP binding / protein kinase A signaling / protein phosphorylation / protein serine kinase activity / endoplasmic reticulum membrane / endoplasmic reticulum / ATP binding / metal ion binding / cytoplasm
Similarity search - Function
cGMP-dependent kinase / cGMP-dependent protein kinase, catalytic domain / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily ...cGMP-dependent kinase / cGMP-dependent protein kinase, catalytic domain / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / RmlC-like jelly roll fold / 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
Similarity search - Domain/homology
Chem-WLK / cGMP-dependent protein kinase
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
Model detailsCo-crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium falciparum in complex ...Co-crystal structure of the cGMP-dependent protein kinase PKG from Plasmodium falciparum in complex with RY-1-165
AuthorsHutchinson, A. / Dong, A. / Seitova, A. / Bhanot, P. / Arrowsmith, C.H. / Edwards, A.M. / Halabelian, L. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.
Authors: Gilleran, J.A. / Ashraf, K. / Delvillar, M. / Eck, T. / Fondekar, R. / Miller, E.B. / Hutchinson, A. / Dong, A. / Seitova, A. / De Souza, M.L. / Augeri, D. / Halabelian, L. / Siekierka, J. / ...Authors: Gilleran, J.A. / Ashraf, K. / Delvillar, M. / Eck, T. / Fondekar, R. / Miller, E.B. / Hutchinson, A. / Dong, A. / Seitova, A. / De Souza, M.L. / Augeri, D. / Halabelian, L. / Siekierka, J. / Rotella, D.P. / Gordon, J. / Childers, W.E. / Grier, M.C. / Staker, B.L. / Roberge, J.Y. / Bhanot, P.
History
DepositionSep 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Aug 7, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cGMP-dependent protein kinase
U: unidentified peptide fragment
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,6317
Polymers98,1732
Non-polymers4585
Water2,738152
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: 1
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)95.145, 127.986, 213.728
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein cGMP-dependent protein kinase / PfPKG


Mass: 97814.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Strain: isolate 3D7 / Gene: PKG, PF3D7_1436600 / Plasmid: pFBOH-MHL / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8I719, cGMP-dependent protein kinase
#2: Protein/peptide unidentified peptide fragment


Mass: 358.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (isolate 3D7) (eukaryote)
Production host: Spodoptera frugiperda (fall armyworm)
#3: Chemical ChemComp-WLK / [(3R)-3-{[(4M)-4-(4-cyclopropyl-2-phenyl-1H-imidazol-1-yl)pyrimidin-2-yl]amino}pyrrolidin-1-yl](1,3-thiazol-2-yl)methanone


Mass: 457.551 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23N7OS / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 4 / Source method: obtained synthetically
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.31 Å3/Da / Density % sol: 62.88 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 20% PEG3350, 0.2M KCL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 11, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.54→50 Å / Num. obs: 44070 / % possible obs: 99.4 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.118 / Rpim(I) all: 0.064 / Rrim(I) all: 0.135 / Χ2: 1.162 / Net I/σ(I): 7.8 / Num. measured all: 180532
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.54-2.583.70.97221720.4790.5681.1311.10299.5
2.58-2.634.20.93921730.5860.4971.0661.06199.7
2.63-2.684.30.79922230.6940.4170.9041.09299.7
2.68-2.744.30.68321430.7420.3580.7741.13199.8
2.74-2.84.30.58721820.8150.3070.6651.10599.7
2.8-2.864.30.49222150.8440.2590.5581.08199.9
2.86-2.934.20.39321730.8910.2070.4451.06799.8
2.93-3.014.20.34321930.9120.1820.3891.1499.8
3.01-3.14.20.27922080.9310.150.3181.13399.9
3.1-3.24.10.22821860.9520.1230.2611.1299.9
3.2-3.314.10.18321940.8490.10.2091.15399.9
3.31-3.4540.14221940.980.0780.1631.2199.6
3.45-3.63.80.11121710.9860.0630.1281.2398.6
3.6-3.793.60.08722030.9880.0510.1011.18499.1
3.79-4.034.30.07122160.9950.0370.081.15299.7
4.03-4.344.30.05821920.9960.030.0661.06499.4
4.34-4.784.20.0522240.9970.0270.0571.09298.8
4.78-5.474.20.05222270.9960.0280.0591.10899.2
5.47-6.893.90.05522540.9950.0310.0631.1798.9
6.89-503.90.06223270.9940.0340.0711.89398

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5DYK

5dyk


Resolution: 2.54→47.65 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.894 / SU B: 19.407 / SU ML: 0.209 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.348 / ESU R Free: 0.264 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2626 2135 4.9 %RANDOM
Rwork0.2183 ---
obs0.2205 41028 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 118.96 Å2 / Biso mean: 42.523 Å2 / Biso min: 9.27 Å2
Baniso -1Baniso -2Baniso -3
1--2.61 Å20 Å2-0 Å2
2--0.45 Å2-0 Å2
3---2.17 Å2
Refinement stepCycle: final / Resolution: 2.54→47.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5917 0 37 152 6106
Biso mean--47.85 38.62 -
Num. residues----783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0136145
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175555
X-RAY DIFFRACTIONr_angle_refined_deg1.2021.6368348
X-RAY DIFFRACTIONr_angle_other_deg1.1691.57712758
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6145794
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.59322.271295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.2615989
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5591536
X-RAY DIFFRACTIONr_chiral_restr0.0430.2851
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.027132
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021328
LS refinement shellResolution: 2.54→2.606 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 164 -
Rwork0.323 2986 -
all-3150 -
obs--99.68 %
Refinement TLS params.Method: refined / Origin x: -5.378 Å / Origin y: -35.019 Å / Origin z: 20.949 Å
111213212223313233
T0.1256 Å2-0.0054 Å2-0.0433 Å2-0.0686 Å20.0014 Å2--0.0193 Å2
L0.6438 °2-0.023 °2-0.0599 °2-1.0405 °20.1984 °2--0.1325 °2
S-0.0249 Å °-0.1962 Å °-0.0017 Å °0.228 Å °0.0309 Å °-0.0744 Å °-0.0147 Å °0.0501 Å °-0.006 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A28 - 817
2X-RAY DIFFRACTION1A901

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