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- PDB-9sgs: S315G KatG mutant no Heme -

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Basic information

Entry
Database: PDB / ID: 9sgs
TitleS315G KatG mutant no Heme
ComponentsCatalase-peroxidase
KeywordsMETAL BINDING PROTEIN / Catalase / Peoxidase / Enzyme / Heme
Function / homology
Function and homology information


catalase-peroxidase / catalase activity / hydrogen peroxide catabolic process / cellular response to hydrogen peroxide / heme binding / metal ion binding / cytosol
Similarity search - Function
Catalase-peroxidase haem / Peroxidases heam-ligand binding site / Peroxidase, active site / Peroxidases active site signature. / Plant heme peroxidase family profile. / Haem peroxidase / Peroxidase / Peroxidases proximal heme-ligand signature. / Haem peroxidase superfamily
Similarity search - Domain/homology
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsChaplin, A.K. / Allport, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Protein Sci / Year: 2026
Title: Uncovering the structural impact of KatG Ser315 mutations in Mycobacterium tuberculosis via cryo-EM.
Authors: Thomas Allport / Amanda K Chaplin /
Abstract: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for a global health burden affecting over a quarter of the world's population. The increasing prevalence of ...Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for a global health burden affecting over a quarter of the world's population. The increasing prevalence of drug-resistant TB poses a significant threat to current treatment strategies. Isoniazid (INH) is a first-line prodrug used in TB therapy, which requires activation by the catalase-peroxidase enzyme KatG. Upon activation, INH inhibits InhA, thereby disrupting mycolic acid biosynthesis, a crucial process for maintaining Mtb's distinctive, lipid-rich cell wall. The most common naturally occurring resistance-associated mutation in KatG is S315T, though other variants at this position, such as S315G, S315N, S315I, and S315R, have also been reported. In this study, we employ cryo-electron microscopy (cryo-EM) to investigate the structural basis of INH resistance conferred by these KatG variants. We present high-resolution cryo-EM structures that reveal heterogeneity in heme loading among the mutants. Detailed structural analysis highlights alterations in the hydrogen-bonding network and substrate access channel unique to each variant, offering direct comparisons with the wild-type (WT) KatG protein. Our findings provide a molecular explanation for clinical INH resistance and lay the groundwork for the rational design of next-generation anti-TB therapeutics.
History
DepositionAug 22, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Catalase-peroxidase
B: Catalase-peroxidase


Theoretical massNumber of molelcules
Total (without water)168,0782
Polymers168,0782
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Catalase-peroxidase / CP / Peroxidase/catalase


Mass: 84039.203 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: katG, MRA_1919 / Production host: Escherichia coli (E. coli) / References: UniProt: A5U3S7, catalase-peroxidase
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: KatG - Catalase peroxidase / Type: COMPLEX / Details: KatG S315G mutation / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.16 MDa / Experimental value: NO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria) / Cellular location: Cytoplasm
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21
Buffer solutionpH: 7.2
Details: 20mM Potassium phosphate 150mM Sodium Chloride 8mM CHAPSO
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaCl1
28 mMCHAPSOC32H58N2O8S1
312.32 mMPotassium Phosphate dibasicK2HPO41
47.6778 mMPotassium Phosphate MonobasicKH2PO41
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9876

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
9PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 290374 / Symmetry type: POINT
RefinementHighest resolution: 2.77 Å / Cross valid method: NONE
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038856
ELECTRON MICROSCOPYf_angle_d0.59412058
ELECTRON MICROSCOPYf_dihedral_angle_d4.5271216
ELECTRON MICROSCOPYf_chiral_restr0.0391322
ELECTRON MICROSCOPYf_plane_restr0.0061575

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