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-Structure paper
タイトル | Structural Elements Involved in ATP Hydrolysis Inhibition and ATP Synthesis of Tuberculosis and Nontuberculous Mycobacterial F-ATP Synthase Decipher New Targets for Inhibitors. |
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ジャーナル・号・ページ | Antimicrob Agents Chemother, Vol. 66, Issue 12, Page e0105622, Year 2022 |
掲載日 | 2022年12月20日 |
著者 | Chui Fann Wong / Wuan-Geok Saw / Sandip Basak / Mio Sano / Hiroshi Ueno / Hwee Wen Kerk / Dennis Litty / Priya Ragunathan / Thomas Dick / Volker Müller / Hiroyuki Noji / Gerhard Grüber / |
PubMed 要旨 | The FF-ATP synthase is required for the viability of tuberculosis (TB) and nontuberculous mycobacteria (NTM) and has been validated as a drug target. Here, we present the cryo-EM structures of the ...The FF-ATP synthase is required for the viability of tuberculosis (TB) and nontuberculous mycobacteria (NTM) and has been validated as a drug target. Here, we present the cryo-EM structures of the Mycobacterium smegmatis F-ATPase and the FF-ATP synthase with different nucleotide occupation within the catalytic sites and visualize critical elements for latent ATP hydrolysis and efficient ATP synthesis. Mutational studies reveal that the extended C-terminal domain (αCTD) of subunit α is the main element for the self-inhibition mechanism of ATP hydrolysis for TB and NTM bacteria. Rotational studies indicate that the transition between the inhibition state by the αCTD and the active state is a rapid process. We demonstrate that the unique mycobacterial γ-loop and subunit δ are critical elements required for ATP formation. The data underline that these mycobacterium-specific elements of α, γ, and δ are attractive targets, providing a platform for the discovery of species-specific inhibitors. |
リンク | Antimicrob Agents Chemother / PubMed:36445139 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.5 - 7.3 Å |
構造データ | EMDB-33614, PDB-7y5a: EMDB-33615, PDB-7y5b: EMDB-33616, PDB-7y5c: EMDB-33617, PDB-7y5d: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-ADP: |
由来 |
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キーワード | HYDROLASE / Complex / F-ATP synthase / cryo-EM / mycobacteria |