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- PDB-8uqv: Trehalose Synthase (TreS) of Mycobacterium tuberculosis in comple... -

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Basic information

Entry
Database: PDB / ID: 8uqv
TitleTrehalose Synthase (TreS) of Mycobacterium tuberculosis in complex with 6-TreAz compound
ComponentsTrehalose synthase/amylase TreS
KeywordsCYTOSOLIC PROTEIN / TreS / Trehalose Synthase / Mycobacterium tuberculosis / 6-TreAz
Function / homology
Function and homology information


maltose alpha-D-glucosyltransferase / maltose alpha-D-glucosyltransferase activity / capsule polysaccharide biosynthetic process / alpha-amylase / glycogen biosynthetic process / alpha-amylase activity / polysaccharide catabolic process / metal ion binding
Similarity search - Function
Trehalose synthase/alpha-amylase, N-terminal / Maltogenic Amylase, C-terminal / Maltogenic Amylase, C-terminal domain / Oligo-1,6-glucosidase, domain 2 / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
alpha-D-glucopyranose / : / Trehalose synthase/amylase TreS
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsPathirage, R. / Ronning, D.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI105084 United States
CitationJournal: ACS Infect Dis / Year: 2024
Title: Targeting Persistence through Inhibition of the Trehalose Catalytic Shift.
Authors: Karishma Kalera / Rachel Liu / Juhyeon Lim / Rasangi Pathirage / Daniel H Swanson / Ulysses G Johnson / Alicyn I Stothard / Jae Jin Lee / Anne W Poston / Peter J Woodruff / Donald R Ronning ...Authors: Karishma Kalera / Rachel Liu / Juhyeon Lim / Rasangi Pathirage / Daniel H Swanson / Ulysses G Johnson / Alicyn I Stothard / Jae Jin Lee / Anne W Poston / Peter J Woodruff / Donald R Ronning / Hyungjin Eoh / Benjamin M Swarts /
Abstract: Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely ...Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb's ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.
History
DepositionOct 24, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Apr 24, 2024Group: 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: Trehalose synthase/amylase TreS
B: Trehalose synthase/amylase TreS
C: Trehalose synthase/amylase TreS
D: Trehalose synthase/amylase TreS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)264,87216
Polymers263,1704
Non-polymers1,70212
Water1,44180
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Trehalose synthase/amylase TreS


Mass: 65792.586 Da / Num. of mol.: 4 / Fragment: residues 12-586
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: treS / Production host: Escherichia coli (E. coli) / References: UniProt: P9WQ18
#2: Sugar
ChemComp-GLC / alpha-D-glucopyranose / alpha-D-glucose / D-glucose / glucose / Glucose


Type: D-saccharide, alpha linking / Mass: 180.156 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H12O6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
a-D-glucopyranoseCOMMON NAMEGMML 1.0
a-D-GlcpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical
ChemComp-XVC / 6-azido-6-deoxy-alpha-D-glucopyranose


Mass: 205.169 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H11N3O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 80 / 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: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5 / Details: 50 mM Tris pH 7.5, 300 mM NaCl and 0.3 mM TCEP
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingAverage exposure time: 1.99734 sec. / Electron dose: 1.06 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 195445 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00418500
ELECTRON MICROSCOPYf_angle_d0.58525248
ELECTRON MICROSCOPYf_dihedral_angle_d4.9222460
ELECTRON MICROSCOPYf_chiral_restr0.0432636
ELECTRON MICROSCOPYf_plane_restr0.0053344

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