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	Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I.
ジャーナル・号・ページ	J Biol Chem, Vol. 298, Issue 3, Page 101602, Year 2022
掲載日	2022年1月19日
著者	Daniel N Grba / James N Blaza / Hannah R Bridges / Ahmed-Noor A Agip / Zhan Yin / Masatoshi Murai / Hideto Miyoshi / Judy Hirst /
PubMed 要旨	Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton ...Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. High-resolution single-particle electron cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, with channel residues likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the structure (determined by cryo-EM) of mouse complex I with a tight-binding natural product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure-activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound but stabilizes the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product.
リンク	J Biol Chem / PubMed:35063503 / PubMed Central
手法	EM (単粒子)
解像度	3.4 Å
構造データ	13611 7psa EMDB-13611, PDB-7psa: The acetogenin-bound complex I of Mus musculus resolved to 3.4 angstroms 手法: EM (単粒子) / 解像度: 3.4 Å
化合物	ChemComp-SF4: IRON/SULFUR CLUSTER ChemComp-PC1: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / リン脂質YM ChemComp-FES: FE2/S2 (INORGANIC) CLUSTER ChemComp-FMN: FLAVIN MONONUCLEOTIDE / FMN ChemComp-3PE: 1,2-Distearoyl-sn-glycerophosphoethanolamine / DSPE / リン脂質YM ChemComp-88I: (3~{S},5~{S})-5-methyl-3-[(13~{R})-13-oxidanyl-13-[(2~{R},5~{R})-5-[(2~{R},5~{R})-5-[(1~{R})-1-oxidanylundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]oxolan-2-one ChemComp-CDL: CARDIOLIPIN / リン脂質YM ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP / ATP, エネルギー貯蔵分子YM ChemComp-NDP: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / NADPH ChemComp-ZN: Unknown entry ChemComp-EHZ: ~{S}-[2-[3-[[(2~{R})-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butanoyl]amino]propanoylamino]ethyl] (3~{S})-3-oxidanyltetradecanethioate
由来	mus musculus (ハツカネズミ) house mouse (ハツカネズミ) Mouse (ネズミ)
キーワード	MEMBRANE PROTEIN / inhibitor-bound / detergent-solubilised / NADH:Ubiquinone oxidoreductase