EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.
ジャーナル・号・ページ	Proc Natl Acad Sci U S A, Vol. 117, Issue 48, Page 30423-30432, Year 2020
掲載日	2020年12月1日
著者	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 /
PubMed 要旨	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.
リンク	Proc Natl Acad Sci U S A / PubMed:33199626 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	2.901 - 4.38 Å
構造データ	21406 6vvx EMDB-21406, PDB-6vvx: Mycobacterium tuberculosis WT RNAP transcription initiation intermediate structure with Sorangicin 手法: EM (単粒子) / 解像度: 3.39 Å 21407 6vvy EMDB-21407, PDB-6vvy: Mycobacterium tuberculosis WT RNAP transcription open promoter complex with Sorangicin 手法: EM (単粒子) / 解像度: 3.42 Å 21408 6vvz EMDB-21408, PDB-6vvz: Mycobacterium tuberculosis RNAP S456L mutant transcription initiation intermediate structure with Sorangicin 手法: EM (単粒子) / 解像度: 3.72 Å 21409 6vw0 EMDB-21409, PDB-6vw0: Mycobacterium tuberculosis RNAP S456L mutant open promoter complex 手法: EM (単粒子) / 解像度: 3.59 Å EMDB-22573: Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - PreRP2 class 手法: EM (単粒子) / 解像度: 4.26 Å EMDB-22575: Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RP2 class 手法: EM (単粒子) / 解像度: 3.53 Å EMDB-22577: Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RPo class 手法: EM (単粒子) / 解像度: 3.35 Å EMDB-22578: Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - PreRP2 class 手法: EM (単粒子) / 解像度: 4.38 Å EMDB-22579: Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RP2 class 手法: EM (単粒子) / 解像度: 3.69 Å EMDB-22580: Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RPo class 手法: EM (単粒子) / 解像度: 3.74 Å PDB-6vvs: Crystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with antibiotic Sorangicin 手法: X-RAY DIFFRACTION / 解像度: 3.112 Å PDB-6vvt: Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and antibiotic Sorangicin 手法: X-RAY DIFFRACTION / 解像度: 2.901 Å PDB-6vvv: Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase 手法: X-RAY DIFFRACTION / 解像度: 3.2 Å
化合物	ChemComp-SO4: SULFATE ION / 硫酸ジアニオン ChemComp-EDO: 1,2-ETHANEDIOL / エチレングリコ-ル ChemComp-SRN: SORANGICIN A ChemComp-ZN: Unknown entry ChemComp-HOH: WATER ChemComp-MG: Unknown entry / マグネシウムジカチオン
由来	mycobacterium tuberculosis (結核菌) mycolicibacterium smegmatis (strain atcc 700084 / mc(2)155) (バクテリア) synthetic construct (人工物)
キーワード	TRANSCRIPTION / TRANSFERASE/DNA/ANTIBIOTIC / DNA binding / antibiotic / TRANSFERASE-DNA-ANTIBIOTIC complex / TRANSFERASE/DNA / TRANSFERASE-DNA complex / initiation / transcription bubble / sorangicin / open promoter complex