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Structure paper

TitleStructure of inhibitor-bound mammalian complex I.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 5261, Year 2020
Publish dateOct 16, 2020
AuthorsHannah R Bridges / Justin G Fedor / James N Blaza / Andrea Di Luca / Alexander Jussupow / Owen D Jarman / John J Wright / Ahmed-Noor A Agip / Ana P Gamiz-Hernandez / Maxie M Roessler / Ville R I Kaila / Judy Hirst /
PubMed AbstractRespiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power ...Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I.
External linksNat Commun / PubMed:33067417 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.1 Å
Structure data

EMDB-11377, PDB-6zr2:
Cryo-EM structure of respiratory complex I in the active state from Mus musculus at 3.1 A
PDB-6ztq: Cryo-EM structure of respiratory complex I from Mus musculus inhibited by piericidin A at 3.0 A
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-11424, PDB-6ztq:
Cryo-EM structure of respiratory complex I from Mus musculus inhibited by piericidin A at 3.0 A
PDB-6zr2: Cryo-EM structure of respiratory complex I in the active state from Mus musculus at 3.1 A
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-11425: Cryo-EM structure of respiratory complex I from Mus musculus inhibited by piericidin A at 3.0 A (Falcon 3)
PDB-6zr2: Cryo-EM structure of respiratory complex I in the active state from Mus musculus at 3.1 A
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-SF4:
IRON/SULFUR CLUSTER / Iron–sulfur cluster

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM / Phosphatidylcholine

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER / Iron–sulfur cluster

ChemComp-FMN:
FLAVIN MONONUCLEOTIDE / Flavin mononucleotide

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM / Phosphatidylethanolamine

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM / Cardiolipin

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-NDP:
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 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

ChemComp-HQH:
Piericidin A / antibiotic*YM / Piericidin A

Source
  • mus musculus (house mouse)
  • Mouse (mice)
KeywordsOXIDOREDUCTASE / NADH / ubiquinone / complex I

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