6VVS

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

Summary for 6VVS

• Entry DOI: 10.2210/pdb6vvs/pdb
• Descriptor: DNA-directed RNA polymerase subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (14 entities in total)
• Functional Keywords: dna binding, antibiotic, transcription, transferase-dna-antibiotic complex, transferase/dna/antibiotic
• Biological source: Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155); More
• Total number of polymer chains: 11
• Total formula weight: 487145.74

Authors

Lilic, M.,Braffman, N.,Darst, S.A.,Campbell, E.A. (deposition date: 2020-02-18, release date: 2020-10-21, Last modification date: 2023-10-11)

Primary citation

Lilic, M.,Chen, J.,Boyaci, H.,Braffman, N.,Hubin, E.A.,Herrmann, J.,Muller, R.,Mooney, R.,Landick, R.,Darst, S.A.,Campbell, E.A.
The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase.
Proc.Natl.Acad.Sci.USA, 117:30423-30432, 2020

PubMed 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 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.

PubMed: 33199626
DOI: 10.1073/pnas.2013706117

Experimental method

X-RAY DIFFRACTION (3.112 Å)