6vvs

Crystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with antibiotic SorangicinCrystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with antibiotic Sorangicin

Structural highlights 6vvs is a 11 chain structure with sequence from Mycolicibacterium smegmatis MC2 155 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.112Å Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RPOA_MYCS2 DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.[HAMAP-Rule:MF_00059] Publication Abstract from PubMed Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen Mycobacterium tuberculosis (Mtb). The emergence of Rif-resistant (Rif(R)) Mtb 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(R) RNAPs, including the most prevalent clinical Rif(R) RNAP substitution found in Mtb infected patients (S456>L of the beta subunit). Here, we present structural and biochemical data demonstrating that Sor inhibits the wild-type Mtb RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the Rif(R) 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. The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase.,Lilic M, Chen J, Boyaci H, Braffman N, Hubin EA, Herrmann J, Muller R, Mooney R, Landick R, Darst SA, Campbell EA Proc Natl Acad Sci U S A. 2020 Nov 16. pii: 2013706117. doi:, 10.1073/pnas.2013706117. PMID:33199626 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also RNA polymerase 3D structures

spinqualitylabelsall models 6vvs, resolution 3.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image