6CCV

Crystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with inhibitor Rifampicin

6CCV の概要

• エントリーDOI: 10.2210/pdb6ccv/pdb
• 分子名称: DNA-directed RNA polymerase subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (15 entities in total)
• 機能のキーワード: dna-directed rna polymerase tuberculosis inhibitor antibiotic transcription initiation, transcription
• 由来する生物種: Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155); 詳細
• タンパク質・核酸の鎖数: 11
• 化学式量合計: 487274.79

構造登録者

Lilic, M.,Darst, S.A.,Campbell, E.A. (登録日: 2018-02-07, 公開日: 2018-08-15, 最終更新日: 2023-10-04)

主引用文献

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

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: 30297823
DOI: 10.1038/s41467-018-06587-2

実験手法

X-RAY DIFFRACTION (3.05 Å)