Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I.
Journal, issue, pages	J Biol Chem, Vol. 298, Issue 3, Page 101602, Year 2022
Publish date	Jan 19, 2022
Authors	Daniel N Grba / James N Blaza / Hannah R Bridges / Ahmed-Noor A Agip / Zhan Yin / Masatoshi Murai / Hideto Miyoshi / Judy Hirst /
PubMed Abstract	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.
External links	J Biol Chem / PubMed:35063503 / PubMed Central
Methods	EM (single particle)
Resolution	3.4 Å
Structure data	13611 7psa EMDB-13611, PDB-7psa: The acetogenin-bound complex I of Mus musculus resolved to 3.4 angstroms Method: EM (single particle) / Resolution: 3.4 Å
Chemicals	ChemComp-SF4: IRON/SULFUR CLUSTER ChemComp-PC1: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipidYM ChemComp-FES: FE2/S2 (INORGANIC) CLUSTER ChemComp-FMN: FLAVIN MONONUCLEOTIDE ChemComp-3PE: 1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipidYM 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 / phospholipidYM ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM ChemComp-NDP: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE 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
Source	mus musculus (house mouse) house mouse (house mouse) Mouse (mice)
Keywords	MEMBRANE PROTEIN / inhibitor-bound / detergent-solubilised / NADH:Ubiquinone oxidoreductase