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Yorodumi- EMDB-42478: Trehalose Synthase (TreS) of Mycobacterium tuberculosis in comple... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-42478 | |||||||||
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Title | Trehalose Synthase (TreS) of Mycobacterium tuberculosis in complex with 6-TreAz compound | |||||||||
Map data | ||||||||||
Sample |
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Keywords | TreS / 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 | |||||||||
Biological species | Mycobacterium tuberculosis (bacteria) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Pathirage R / Ronning DR | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_42478.map.gz | 203.9 MB | EMDB map data format | |
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Header (meta data) | emd-42478-v30.xml emd-42478.xml | 15.6 KB 15.6 KB | Display Display | EMDB header |
Images | emd_42478.png | 100.1 KB | ||
Filedesc metadata | emd-42478.cif.gz | 6 KB | ||
Others | emd_42478_half_map_1.map.gz emd_42478_half_map_2.map.gz | 200.3 MB 200.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-42478 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-42478 | HTTPS FTP |
-Validation report
Summary document | emd_42478_validation.pdf.gz | 981.5 KB | Display | EMDB validaton report |
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Full document | emd_42478_full_validation.pdf.gz | 981.1 KB | Display | |
Data in XML | emd_42478_validation.xml.gz | 15.6 KB | Display | |
Data in CIF | emd_42478_validation.cif.gz | 18.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-42478 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-42478 | HTTPS FTP |
-Related structure data
Related structure data | 8uqvMC 8uzhC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_42478.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.13 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_42478_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_42478_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
Entire | Name: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis |
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Components |
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-Supramolecule #1: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis
Supramolecule | Name: 6-TreAz bound Trehalose synthase of Mycobacterium tuberculosis type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Mycobacterium tuberculosis (bacteria) |
-Macromolecule #1: Trehalose synthase/amylase TreS
Macromolecule | Name: Trehalose synthase/amylase TreS / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Mycobacterium tuberculosis (bacteria) |
Molecular weight | Theoretical: 65.792586 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 |
-Macromolecule #2: alpha-D-glucopyranose
Macromolecule | Name: alpha-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 4 / Formula: GLC |
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Molecular weight | Theoretical: 180.156 Da |
Chemical component information | ChemComp-GLC: |
-Macromolecule #3: 6-azido-6-deoxy-alpha-D-glucopyranose
Macromolecule | Name: 6-azido-6-deoxy-alpha-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 4 / Formula: XVC |
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Molecular weight | Theoretical: 205.169 Da |
-Macromolecule #4: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #5: water
Macromolecule | Name: water / type: ligand / ID: 5 / Number of copies: 80 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.5 mg/mL |
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Buffer | pH: 7.5 / Details: 50 mM Tris pH 7.5, 300 mM NaCl and 0.3 mM TCEP |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % |
-Electron microscopy
Microscope | TFS GLACIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.99734 sec. / Average electron dose: 1.06 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 195445 |
Initial angle assignment | Type: NOT APPLICABLE |
Final angle assignment | Type: NOT APPLICABLE |