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- PDB-8q17: Identification and optimisation of novel inhibitors of the Polyke... -

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Basic information

Entry
Database: PDB / ID: 8q17
TitleIdentification and optimisation of novel inhibitors of the Polyketide synthetase 13 thioesterase domain with antitubercular activity
ComponentsPolyketide synthase Pks13
KeywordsTRANSFERASE / inhibitor complex
Function / homology
Function and homology information


periplasmic space / electron transfer activity / copper ion binding
Similarity search - Function
Azurin / : / Blue (type 1) copper domain / Copper binding proteins, plastocyanin/azurin family / Blue (type 1) copper protein, binding site / Type-1 copper (blue) proteins signature. / Cupredoxin
Similarity search - Domain/homology
Chem-2Q5 / Chem-IL8 / Azurin iso-2
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.71 Å
AuthorsEadsforth, T.C. / Punekar, A.S. / Green, S.R. / Baragana, B.
Funding support United Kingdom, United States, 2items
OrganizationGrant numberCountry
Wellcome Trust100195/Z/12/Z United Kingdom
Bill & Melinda Gates FoundationOPP1066891 United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.
Authors: Green, S.R. / Wilson, C. / Eadsforth, T.C. / Punekar, A.S. / Tamaki, F.K. / Wood, G. / Caldwell, N. / Forte, B. / Norcross, N.R. / Kiczun, M. / Post, J.M. / Lopez-Roman, E.M. / Engelhart, C. ...Authors: Green, S.R. / Wilson, C. / Eadsforth, T.C. / Punekar, A.S. / Tamaki, F.K. / Wood, G. / Caldwell, N. / Forte, B. / Norcross, N.R. / Kiczun, M. / Post, J.M. / Lopez-Roman, E.M. / Engelhart, C.A. / Lukac, I. / Zuccotto, F. / Epemolu, O. / Boshoff, H.I.M. / Schnappinger, D. / Walpole, C. / Gilbert, I.H. / Read, K.D. / Wyatt, P.G. / Baragana, B.
History
DepositionJul 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 6, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Polyketide synthase Pks13
B: Polyketide synthase Pks13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,34312
Polymers63,5552
Non-polymers1,78810
Water6,125340
1
A: Polyketide synthase Pks13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5946
Polymers31,7781
Non-polymers8175
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Polyketide synthase Pks13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7496
Polymers31,7781
Non-polymers9715
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.450, 109.846, 57.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Polyketide synthase Pks13


Mass: 31777.742 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Strain: (strain ATCC 25618 / H37Rv) / Gene: pks13, Rv3800c / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: I6X8D2, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups

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Non-polymers , 5 types, 350 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-IL8 / ~{N}-[2-[4-(azetidin-1-ylcarbonyl)phenyl]ethyl]-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole-5-carboxamide


Mass: 436.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24N4O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-2Q5 / (2R)-2-{[(2R)-2-{[(2S)-2-{[(2R)-2-hydroxypropyl]oxy}propyl]oxy}propyl]oxy}propan-1-ol


Mass: 250.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.2 Å3/Da / Density % sol: 44.21 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M Tris-HCl pH 8.5, 1.8 M Ammonium sulfate, 3% v/v PPG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Sep 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.709→88.46 Å / Num. obs: 56541 / % possible obs: 92 % / Redundancy: 11.6 % / CC1/2: 0.995 / Net I/σ(I): 12.6
Reflection shellResolution: 1.709→1.77 Å / Num. unique obs: 3520 / CC1/2: 0.764

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.71→88.45 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.944 / SU B: 3.779 / SU ML: 0.114 / Cross valid method: THROUGHOUT / ESU R: 0.131 / ESU R Free: 0.128 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23869 2738 4.9 %RANDOM
Rwork0.19531 ---
obs0.19742 53377 91.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.171 Å2
Baniso -1Baniso -2Baniso -3
1--0.57 Å20 Å20 Å2
2---0.62 Å20 Å2
3---1.18 Å2
Refinement stepCycle: 1 / Resolution: 1.71→88.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4321 0 118 340 4779
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0194569
X-RAY DIFFRACTIONr_bond_other_d0.0020.024203
X-RAY DIFFRACTIONr_angle_refined_deg1.9731.9856202
X-RAY DIFFRACTIONr_angle_other_deg1.10339699
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2395558
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.53723.288222
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.3715712
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6081544
X-RAY DIFFRACTIONr_chiral_restr0.120.2657
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0215127
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02963
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.0663.1062223
X-RAY DIFFRACTIONr_mcbond_other3.0643.1042222
X-RAY DIFFRACTIONr_mcangle_it4.2974.6422778
X-RAY DIFFRACTIONr_mcangle_other4.2974.6442779
X-RAY DIFFRACTIONr_scbond_it3.9883.5332346
X-RAY DIFFRACTIONr_scbond_other3.9873.5342347
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9455.1473419
X-RAY DIFFRACTIONr_long_range_B_refined7.56437.3585190
X-RAY DIFFRACTIONr_long_range_B_other7.56437.3665191
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.71→1.754 Å
RfactorNum. reflection% reflection
Rfree0.343 136 -
Rwork0.314 2397 -
obs--56.25 %

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