6CCE
Crystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with inhibitor Kanglemycin A
Summary for 6CCE
| Entry DOI | 10.2210/pdb6cce/pdb |
| Descriptor | RNA polymerase-binding protein RbpA, SULFATE ION, ZINC ION, ... (14 entities in total) |
| Functional Keywords | rna polymerase antibiotic complex inhibitor tuberculosis, transcription, transcription-antibiotic complex, transcription-dna-antibiotic complex, transcription/dna/antibiotic |
| Biological source | Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155) More |
| Total number of polymer chains | 9 |
| Total formula weight | 448861.88 |
| Authors | Lilic, M.,Darst, S.A.,Campbell, E.A. (deposition date: 2018-02-07, release date: 2018-08-15, Last modification date: 2023-10-04) |
| Primary citation | Peek, J.,Lilic, M.,Montiel, D.,Milshteyn, A.,Woodworth, I.,Biggins, J.B.,Ternei, M.A.,Calle, P.Y.,Danziger, M.,Warrier, T.,Saito, K.,Braffman, N.,Fay, A.,Glickman, M.S.,Darst, S.A.,Campbell, E.A.,Brady, S.F. Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism. Nat Commun, 9:4147-4147, 2018 Cited by PubMed Abstract: Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms. PubMed: 30297823DOI: 10.1038/s41467-018-06587-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.05 Å) |
Structure validation
Download full validation report
