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- EMDB-21406: Mycobacterium tuberculosis WT RNAP transcription initiation inter... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-21406 | |||||||||
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Title | Mycobacterium tuberculosis WT RNAP transcription initiation intermediate structure with Sorangicin | |||||||||
![]() | Mycobacterium tuberculosis WT RNAP transcription initiation intermediate structure with Sorangicin | |||||||||
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![]() | initiation / transcription bubble / antibiotic / sorangicin / open promoter complex / TRANSCRIPTION / TRANSFERASE-DNA-ANTIBIOTIC complex | |||||||||
Function / homology | ![]() bacterial-type RNA polymerase holo enzyme binding / response to water / Antimicrobial action and antimicrobial resistance in Mtb / bacterial-type RNA polymerase core enzyme binding / sigma factor activity / rRNA transcription / DNA-directed RNA polymerase complex / peptidoglycan-based cell wall / DNA-templated transcription initiation / ribonucleoside binding ...bacterial-type RNA polymerase holo enzyme binding / response to water / Antimicrobial action and antimicrobial resistance in Mtb / bacterial-type RNA polymerase core enzyme binding / sigma factor activity / rRNA transcription / DNA-directed RNA polymerase complex / peptidoglycan-based cell wall / DNA-templated transcription initiation / ribonucleoside binding / DNA-directed 5'-3' RNA polymerase activity / DNA-directed RNA polymerase / nucleic acid binding / protein dimerization activity / response to antibiotic / DNA-templated transcription / positive regulation of DNA-templated transcription / magnesium ion binding / DNA binding / zinc ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.39 Å | |||||||||
![]() | Lilic M / Boyaci H | |||||||||
Funding support | ![]()
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![]() | ![]() Title: The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase. Authors: Mirjana Lilic / James Chen / Hande Boyaci / Nathaniel Braffman / Elizabeth A Hubin / Jennifer Herrmann / Rolf Müller / Rachel Mooney / Robert Landick / Seth A Darst / Elizabeth A Campbell / ![]() ![]() Abstract: Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) presents a need for new ...Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) presents a need for new antibiotics. Rif targets the enzyme RNA polymerase (RNAP). Sorangicin A (Sor) is an unrelated inhibitor that binds in the Rif-binding pocket of RNAP. Sor inhibits a subset of Rif RNAPs, including the most prevalent clinical Rif RNAP substitution found in infected patients (S456>L of the β subunit). Here, we present structural and biochemical data demonstrating that Sor inhibits the wild-type RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the Rif S456L enzyme at an earlier step, preventing the transition of a partially unwound promoter DNA intermediate to the fully opened DNA and blocking the template-strand DNA from reaching the active site in the RNAP catalytic center. By defining template-strand blocking as a mechanism for inhibition, we provide a mechanistic drug target in RNAP. Our finding that Sor inhibits the wild-type and mutant RNAPs through different mechanisms prompts future considerations for designing antibiotics against resistant targets. Also, we show that Sor has a better pharmacokinetic profile than Rif, making it a suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 78.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 23.5 KB 23.5 KB | Display Display | ![]() |
Images | ![]() | 175.4 KB | ||
Filedesc metadata | ![]() | 8.6 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6vvxMC ![]() 6vvsC ![]() 6vvtC ![]() 6vvvC ![]() 6vvyC ![]() 6vvzC ![]() 6vw0C C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Mycobacterium tuberculosis WT RNAP transcription initiation intermediate structure with Sorangicin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.1 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
+Entire : Mycobacterium tuberculosis RNAP promoter open complex
+Supramolecule #1: Mycobacterium tuberculosis RNAP promoter open complex
+Macromolecule #1: DNA-directed RNA polymerase subunit alpha
+Macromolecule #2: DNA-directed RNA polymerase subunit beta
+Macromolecule #3: DNA-directed RNA polymerase subunit beta'
+Macromolecule #4: DNA-directed RNA polymerase subunit omega
+Macromolecule #5: RNA polymerase sigma factor SigA
+Macromolecule #6: RNA polymerase-binding protein RbpA
+Macromolecule #8: RNA polymerase-binding transcription factor CarD
+Macromolecule #7: DNA (63-MER)
+Macromolecule #9: DNA (65-MER)
+Macromolecule #10: SORANGICIN A
+Macromolecule #11: ZINC ION
+Macromolecule #12: MAGNESIUM ION
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Grid | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 66.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: EMDB MAP |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.39 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 75398 |
Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: PROJECTION MATCHING |