登録情報 データベース : EMDB / ID : EMD-21408 構造の表示 ダウンロードとリンクタイトル Mycobacterium tuberculosis RNAP S456L mutant transcription initiation intermediate structure with Sorangicin マップデータMycobacterium tuberculosis RNAP S456L mutant transcription initiation intermediate structure with Sorangicin 詳細 試料複合体 : Mycobacterium tuberculosis RNAP S456L mutant promoter melting intermediate complexタンパク質・ペプチド : x 7種DNA : x 2種リガンド : x 3種 詳細 キーワード initiation / transcription bubble / antibiotic / sorangicin / open promoter complex / TRANSCRIPTION / TRANSFERASE-DNA-ANTIBIOTIC complex機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
response to water / bacterial-type RNA polymerase holo enzyme binding / Antimicrobial action and antimicrobial resistance in Mtb / sigma factor activity / bacterial-type RNA polymerase core enzyme binding / rRNA transcription / cytosolic DNA-directed RNA polymerase complex / DNA-directed RNA polymerase complex / peptidoglycan-based cell wall / : ... response to water / bacterial-type RNA polymerase holo enzyme binding / Antimicrobial action and antimicrobial resistance in Mtb / sigma factor activity / bacterial-type RNA polymerase core enzyme binding / rRNA transcription / cytosolic DNA-directed RNA polymerase complex / DNA-directed RNA polymerase complex / peptidoglycan-based cell wall / : / : / : / : / : / : / DNA-templated transcription initiation / DNA-directed RNA polymerase activity / ribonucleoside binding / DNA-directed RNA polymerase / nucleic acid binding / protein dimerization activity / response to antibiotic / DNA-templated transcription / positive regulation of DNA-templated transcription / magnesium ion binding / DNA binding / zinc ion binding / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 CarD-like, C-terminal domain / : / : / CarD, C-terminal domain / RNA polymerase-binding protein RbpA / RbpA superfamily / RNA polymerase-binding protein / CarD-like/TRCF, RNAP-interacting domain / CarD-like/TRCF, RNAP-interacting domain superfamily / CarD-like/TRCF RID domain ... CarD-like, C-terminal domain / : / : / CarD, C-terminal domain / RNA polymerase-binding protein RbpA / RbpA superfamily / RNA polymerase-binding protein / CarD-like/TRCF, RNAP-interacting domain / CarD-like/TRCF, RNAP-interacting domain superfamily / CarD-like/TRCF RID domain / CarD-like/TRCF domain / Sigma-70 factors family signature 1. / RNA polymerase sigma factor RpoD, C-terminal / RNA polymerase sigma factor RpoD / : / RNA polymerase sigma-70 region 1.2 / Sigma-70 factor, region 1.2 / RNA polymerase sigma-70 region 3 / Sigma-70 region 3 / Sigma-70 factors family signature 2. / RNA polymerase sigma-70 / RNA polymerase sigma-70 region 4 / Sigma-70, region 4 / RNA polymerase sigma-70 region 2 / RNA polymerase sigma-70 like domain / Sigma-70 region 2 / RNA polymerase sigma factor, region 2 / RNA polymerase sigma factor, region 3/4-like / DNA-directed RNA polymerase, omega subunit / DNA-directed RNA polymerase, subunit beta-prime, bacterial type / DNA-directed RNA polymerase, beta subunit, external 1 domain superfamily / DNA-directed RNA polymerase, beta subunit, external 1 domain / RNA polymerase beta subunit external 1 domain / RNA polymerase, alpha subunit, C-terminal / Bacterial RNA polymerase, alpha chain C terminal domain / DNA-directed RNA polymerase, alpha subunit / DNA-directed RNA polymerase beta subunit, bacterial-type / DNA-directed RNA polymerase, subunit beta-prime / RNA polymerase Rpb6 / RNA polymerase, subunit omega/Rpo6/RPB6 / RNA polymerase Rpb6 / RNA polymerase Rpb2, domain 2 superfamily / RNA polymerase Rpb1, domain 3 superfamily / RPB6/omega subunit-like superfamily / DNA-directed RNA polymerase, insert domain / DNA-directed RNA polymerase, RpoA/D/Rpb3-type / RNA polymerase Rpb3/RpoA insert domain / RNA polymerase Rpb3/Rpb11 dimerisation domain / RNA polymerases D / RNA polymerase Rpb1, clamp domain superfamily / RNA polymerase Rpb1, domain 3 / RNA polymerase Rpb1, domain 3 / RNA polymerase Rpb1, domain 1 / RNA polymerase, beta subunit, protrusion / RNA polymerase beta subunit / RNA polymerase Rpb1, domain 1 / RNA polymerase, alpha subunit / RNA polymerase Rpb1, domain 5 / RNA polymerase Rpb1, domain 4 / DNA-directed RNA polymerase, insert domain superfamily / RNA polymerase Rpb1, domain 2 / RNA polymerase Rpb1, domain 5 / RNA polymerase Rpb1, domain 4 / RNA polymerase Rpb2, domain 2 / RNA polymerase Rpb2, domain 2 / RNA polymerase, RBP11-like subunit / RNA polymerase, N-terminal / RNA polymerase Rpb1, funnel domain superfamily / RNA polymerase I subunit A N-terminus / RNA polymerase, beta subunit, conserved site / RNA polymerase Rpb2, domain 7 / RNA polymerase Rpb2, domain 3 / RNA polymerase Rpb2, OB-fold / RNA polymerase Rpb2, domain 7 / RNA polymerase Rpb2, domain 3 / RNA polymerases beta chain signature. / DNA-directed RNA polymerase, subunit 2, hybrid-binding domain / DNA-directed RNA polymerase, subunit 2 / DNA-directed RNA polymerase, subunit 2, hybrid-binding domain superfamily / RNA polymerase Rpb2, domain 6 / Winged helix-like DNA-binding domain superfamily 類似検索 - ドメイン・相同性 DNA-directed RNA polymerase subunit omega / DNA-directed RNA polymerase subunit beta' / DNA-directed RNA polymerase subunit alpha / RNA polymerase sigma factor SigA / RNA polymerase sigma factor SigA / DNA-directed RNA polymerase subunit omega / DNA-directed RNA polymerase subunit beta' / DNA-directed RNA polymerase subunit beta / DNA-directed RNA polymerase subunit alpha / RNA polymerase-binding protein RbpA ... DNA-directed RNA polymerase subunit omega / DNA-directed RNA polymerase subunit beta' / DNA-directed RNA polymerase subunit alpha / RNA polymerase sigma factor SigA / RNA polymerase sigma factor SigA / DNA-directed RNA polymerase subunit omega / DNA-directed RNA polymerase subunit beta' / DNA-directed RNA polymerase subunit beta / DNA-directed RNA polymerase subunit alpha / RNA polymerase-binding protein RbpA / RNA polymerase-binding protein RbpA / RNA polymerase-binding transcription factor CarD / RNA polymerase-binding transcription factor CarD / DNA-directed RNA polymerase subunit beta 類似検索 - 構成要素生物種 Mycobacterium tuberculosis (結核菌)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.72 Å 詳細 データ登録者Lilic M / Boyaci H 資金援助 米国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) 米国
引用ジャーナル : Proc Natl Acad Sci U S A / 年 : 2020タイトル : The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.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 / 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. 履歴 登録 2020年2月18日 - ヘッダ(付随情報) 公開 2020年3月18日 - マップ公開 2020年10月21日 - 更新 2025年5月21日 - 現状 2025年5月21日 処理サイト : RCSB / 状態 : 公開
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