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- PDB-8q0u: Identification and optimisation of novel inhibitors of the Polyke... -

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Basic information

Entry
Database: PDB / ID: 8q0u
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


DIM/DIP cell wall layer assembly / fatty acid synthase activity / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / fatty acid biosynthetic process / cytoplasm
Similarity search - Function
Thioesterase / Thioesterase domain / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Malonyl-CoA ACP transacylase, ACP-binding / Acyl transferase domain superfamily / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase/acyl hydrolase/lysophospholipase ...Thioesterase / Thioesterase domain / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Malonyl-CoA ACP transacylase, ACP-binding / Acyl transferase domain superfamily / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase/acyl hydrolase/lysophospholipase / Ketosynthase family 3 (KS3) domain profile. / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / Beta-ketoacyl synthase / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase, N-terminal / Beta-ketoacyl synthase, C-terminal / Beta-ketoacyl synthase, N-terminal domain / Beta-ketoacyl synthase, C-terminal domain / Thiolase-like / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-IKG / Polyketide synthase Pks13
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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 29, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)64,6716
Polymers63,5552
Non-polymers1,1154
Water7,422412
1
A: Polyketide synthase Pks13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3353
Polymers31,7781
Non-polymers5582
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Polyketide synthase Pks13
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3353
Polymers31,7781
Non-polymers5582
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.565, 108.606, 57.525
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#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) / Gene: pks13, Rv3800c / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: I6X8D2, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 461.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23N5O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 412 / 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: 2.24 Å3/Da / Density % sol: 45.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1M Tris-HCl pH 8.5, 1.8 M Ammonium sulfate, 3% PPG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Feb 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.8→68.17 Å / Num. obs: 48490 / % possible obs: 93.8 % / Redundancy: 7.1 % / CC1/2: 0.93 / Net I/σ(I): 4.1
Reflection shellResolution: 1.8→1.84 Å / Num. unique obs: 3026 / CC1/2: 0.54

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
autoPROCdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→68.17 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.94 / SU B: 3.891 / SU ML: 0.115 / Cross valid method: THROUGHOUT / ESU R: 0.152 / ESU R Free: 0.143 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23459 2430 5 %RANDOM
Rwork0.18923 ---
obs0.19146 45754 93.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.296 Å2
Baniso -1Baniso -2Baniso -3
1-0.49 Å20 Å20 Å2
2---1 Å20 Å2
3---0.5 Å2
Refinement stepCycle: 1 / Resolution: 1.8→68.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4298 0 78 412 4788
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0194506
X-RAY DIFFRACTIONr_bond_other_d0.0020.024129
X-RAY DIFFRACTIONr_angle_refined_deg1.861.966121
X-RAY DIFFRACTIONr_angle_other_deg1.0592.9859529
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0615553
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.96622.965226
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.2815704
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2361543
X-RAY DIFFRACTIONr_chiral_restr0.1110.2645
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0215105
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02956
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_it2.6792.7822212
X-RAY DIFFRACTIONr_mcbond_other2.6762.782211
X-RAY DIFFRACTIONr_mcangle_it3.7024.1512765
X-RAY DIFFRACTIONr_mcangle_other3.7034.1532766
X-RAY DIFFRACTIONr_scbond_it3.5333.2252294
X-RAY DIFFRACTIONr_scbond_other3.5263.2082286
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3394.6643340
X-RAY DIFFRACTIONr_long_range_B_refined7.36134.7035261
X-RAY DIFFRACTIONr_long_range_B_other7.24234.2935158
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 195 -
Rwork0.257 3565 -
obs--99.97 %

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