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- EMDB-42478: Trehalose Synthase (TreS) of Mycobacterium tuberculosis in comple... -

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Basic information

Entry
Database: EMDB / ID: EMD-42478
TitleTrehalose Synthase (TreS) of Mycobacterium tuberculosis in complex with 6-TreAz compound
Map data
Sample
  • Complex: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
    • Protein or peptide: Trehalose synthase/amylase TreS
  • Ligand: alpha-D-glucopyranose
  • Ligand: 6-azido-6-deoxy-alpha-D-glucopyranose
  • Ligand: CALCIUM IONCalcium
  • Ligand: water
KeywordsTreS / Trehalose Synthase / Mycobacterium tuberculosis / 6-TreAz / CYTOSOLIC PROTEIN
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
Trehalose synthase/amylase TreS
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsPathirage R / Ronning DR
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42478.png

Downloads & links

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Map

FileDownload / File: emd_42478.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.13 Å
Density
Contour LevelBy EMDB: 0.3
Minimum - Maximum-1.3986719 - 2.2244437
Average (Standard dev.)0.000433059 (±0.042176493)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 433.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_42478_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_42478_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis

EntireName: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
Components
  • Complex: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
    • Protein or peptide: Trehalose synthase/amylase TreS
  • Ligand: alpha-D-glucopyranose
  • Ligand: 6-azido-6-deoxy-alpha-D-glucopyranose
  • Ligand: CALCIUM IONCalcium
  • Ligand: water

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Supramolecule #1: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis

SupramoleculeName: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)

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Macromolecule #1: Trehalose synthase/amylase TreS

MacromoleculeName: Trehalose synthase/amylase TreS / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Molecular weightTheoretical: 65.792586 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: PVQGSHVEGG VVEHPDAKDF GSAAALPADP TWFKHAVFYE VLVRAFFDAS ADGSGDLRGL IDRLDYLQWL GIDCIWLPPF YDSPLRDGG YDIRDFYKVL PEFGTVDDFV ALVDAAHRRG IRIITDLVMN HTSESHPWFQ ESRRDPDGPY GDYYVWSDTS E RYTDARII ...String:
PVQGSHVEGG VVEHPDAKDF GSAAALPADP TWFKHAVFYE VLVRAFFDAS ADGSGDLRGL IDRLDYLQWL GIDCIWLPPF YDSPLRDGG YDIRDFYKVL PEFGTVDDFV ALVDAAHRRG IRIITDLVMN HTSESHPWFQ ESRRDPDGPY GDYYVWSDTS E RYTDARII FVDTEESNWS FDPVRRQFYW HRFFSHQPDL NYDNPAVQEA MIDVIRFWLG LGIDGFRLAA VPYLFEREGT NC ENLPETH AFLKRVRKVV DDEFPGRVLL AEANQWPGDV VEYFGDPNTG GDECHMAFHF PLMPRIFMAV RRESRFPISE IIA QTPPIP DMAQWGIFLR NHDELTLEMV TDEERDYMYA EYAKDPRMKA NVGIRRRLAP LLDNDRNQIE LFTALLLSLP GSPV LYYGD EIGMGDVIWL GDRDGVRIPM QWTPDRNAGF STANPGRLYL PPSQDPVYGY QAVNVEAQRD TSTSLLNFTR TMLAV RRRH PAFAVGAFQE LGGSNPSVLA YVRQVAGDDG DTVLCVNNLS RFPQPIELDL QQWTNYTPVE LTGHVEFPRI GQVPYL LTL PGHGFYWFQL TT

UniProtKB: Trehalose synthase/amylase TreS

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Macromolecule #2: alpha-D-glucopyranose

MacromoleculeName: alpha-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 4 / Formula: GLC
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-GLC:
alpha-D-glucopyranose / Glucose

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Macromolecule #3: 6-azido-6-deoxy-alpha-D-glucopyranose

MacromoleculeName: 6-azido-6-deoxy-alpha-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: XVC
Molecular weightTheoretical: 205.169 Da

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Macromolecule #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 80 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 7.5 / Details: 50 mM Tris pH 7.5, 300 mM NaCl and 0.3 mM TCEP
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.99734 sec. / Average electron dose: 1.06 e/Å2

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4lxf

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 195445

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