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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of Staphylococcus aureus 70S ribosome (strain 15B196) in complex with MCX-190. | |||||||||
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![]() | ribosome / ANTIBIOTIC | |||||||||
機能・相同性 | ![]() large ribosomal subunit / transferase activity / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / 5S rRNA binding / small ribosomal subunit rRNA binding / ribosomal large subunit assembly / cytosolic small ribosomal subunit / large ribosomal subunit rRNA binding ...large ribosomal subunit / transferase activity / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / 5S rRNA binding / small ribosomal subunit rRNA binding / ribosomal large subunit assembly / cytosolic small ribosomal subunit / large ribosomal subunit rRNA binding / cytosolic large ribosomal subunit / cytoplasmic translation / tRNA binding / negative regulation of translation / rRNA binding / structural constituent of ribosome / ribosome / translation / ribonucleoprotein complex / mRNA binding / RNA binding / zinc ion binding / cytosol / cytoplasm 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.58 Å | |||||||||
![]() | Li Y / Lu G / Li J / Pei X / Lin J | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Synthetic macrolides overcoming MLSK-resistant pathogens. 著者: Cong-Xuan Ma / Ye Li / Wen-Tian Liu / Yun Li / Fei Zhao / Xiao-Tian Lian / Jing Ding / Si-Meng Liu / Xie-Peng Liu / Bing-Zhi Fan / Li-Yong Liu / Feng Xue / Jian Li / Jue-Ru Zhang / Zhao Xue / ...著者: Cong-Xuan Ma / Ye Li / Wen-Tian Liu / Yun Li / Fei Zhao / Xiao-Tian Lian / Jing Ding / Si-Meng Liu / Xie-Peng Liu / Bing-Zhi Fan / Li-Yong Liu / Feng Xue / Jian Li / Jue-Ru Zhang / Zhao Xue / Xiao-Tong Pei / Jin-Zhong Lin / Jian-Hua Liang / ![]() 要旨: Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation ...Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance. | |||||||||
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構造の表示
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ダウンロードとリンク
-EMDBアーカイブ
マップデータ | ![]() | 338.2 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 69 KB 69 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 17 KB | 表示 | ![]() |
画像 | ![]() | 206.3 KB | ||
マスクデータ | ![]() | 421.9 MB | ![]() | |
Filedesc metadata | ![]() | 13.1 KB | ||
その他 | ![]() ![]() | 337.7 MB 338.5 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 1.1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.1 MB | 表示 | |
XML形式データ | ![]() | 24.7 KB | 表示 | |
CIF形式データ | ![]() | 32.8 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8y38MC ![]() 8y36C ![]() 8y37C ![]() 8y39C ![]() 39379 M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 0.824 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
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試料の構成要素
+全体 : Staphylococcus aureus 70S ribosome (strain 15B196) in complex wit...
+超分子 #1: Staphylococcus aureus 70S ribosome (strain 15B196) in complex wit...
+分子 #1: Large ribosomal subunit protein bL33B
+分子 #2: Large ribosomal subunit protein bL34
+分子 #3: Large ribosomal subunit protein bL35
+分子 #4: Large ribosomal subunit protein bL36
+分子 #7: Large ribosomal subunit protein uL2
+分子 #8: Large ribosomal subunit protein uL3
+分子 #9: Large ribosomal subunit protein uL4
+分子 #10: Large ribosomal subunit protein uL5
+分子 #11: Large ribosomal subunit protein uL6
+分子 #12: Large ribosomal subunit protein uL13
+分子 #13: Large ribosomal subunit protein uL14
+分子 #14: Large ribosomal subunit protein uL15
+分子 #15: Large ribosomal subunit protein uL16
+分子 #16: Large ribosomal subunit protein bL17
+分子 #17: Large ribosomal subunit protein uL18
+分子 #18: Large ribosomal subunit protein bL19
+分子 #19: Large ribosomal subunit protein bL20
+分子 #20: Large ribosomal subunit protein bL21
+分子 #21: Large ribosomal subunit protein uL22
+分子 #22: Large ribosomal subunit protein uL23
+分子 #23: Large ribosomal subunit protein uL24
+分子 #24: Large ribosomal subunit protein bL25
+分子 #25: Large ribosomal subunit protein bL27
+分子 #26: Large ribosomal subunit protein bL28
+分子 #27: Large ribosomal subunit protein uL29
+分子 #28: Large ribosomal subunit protein uL30
+分子 #29: Large ribosomal subunit protein bL31B
+分子 #30: Large ribosomal subunit protein bL32
+分子 #32: Small ribosomal subunit protein uS2
+分子 #33: Small ribosomal subunit protein uS3
+分子 #34: Small ribosomal subunit protein uS4
+分子 #35: Small ribosomal subunit protein uS5
+分子 #36: Small ribosomal subunit protein bS6
+分子 #37: Small ribosomal subunit protein uS7
+分子 #38: Small ribosomal subunit protein uS8
+分子 #39: Small ribosomal subunit protein uS9
+分子 #40: Small ribosomal subunit protein uS10
+分子 #41: Small ribosomal subunit protein uS11
+分子 #42: Small ribosomal subunit protein uS12
+分子 #43: Small ribosomal subunit protein uS13
+分子 #44: Small ribosomal subunit protein uS14B
+分子 #45: Small ribosomal subunit protein uS15
+分子 #46: Small ribosomal subunit protein bS16
+分子 #47: Small ribosomal subunit protein uS17
+分子 #48: Small ribosomal subunit protein bS18
+分子 #49: Small ribosomal subunit protein uS19
+分子 #50: Small ribosomal subunit protein bS20
+分子 #5: 23S ribosomal RNA
+分子 #6: 5S ribosomal RNA
+分子 #31: 16S ribosomal RNA
+分子 #51: 7-[4-[3-[[(1~{S},2~{R},5~{R},6~{S},7~{S},8~{R},9~{R},11~{R},13~{R...
+分子 #52: MAGNESIUM ION
+分子 #53: water
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.4 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 50.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.5 µm / 最小 デフォーカス(公称値): 0.5 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
初期モデル | モデルのタイプ: OTHER |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.58 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 47560 |
初期 角度割当 | タイプ: ANGULAR RECONSTITUTION |
最終 角度割当 | タイプ: ANGULAR RECONSTITUTION |