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Structure paper

TitleGlobal conformations of complex I are distinguished by the binding of a unique interdomain bridging subunit.
Journal, issue, pagesSci Adv, Vol. 11, Issue 40, Page eadz0693, Year 2025
Publish dateOct 3, 2025
AuthorsChris Seunggyu Lee / Daniel N Grba / John J Wright / Bozhidar S Ivanov / Judy Hirst /
PubMed AbstractComplex I (CI; NADH ubiquinone oxidoreductase) is central to energy generation and metabolic homeostasis in mammalian cells but contributes to adverse outcome pathways under challenging conditions. ...Complex I (CI; NADH ubiquinone oxidoreductase) is central to energy generation and metabolic homeostasis in mammalian cells but contributes to adverse outcome pathways under challenging conditions. During ischemia, mammalian CI transitions from a turnover-ready, structurally "closed" state toward a dormant "open" state that prevents it from functioning in reverse during reperfusion to produce reactive oxygen species. Unfortunately, simpler, genetically tractable CI models do not recapitulate the same regulatory behavior, compromising mechanistic studies. Here, we report the structure of isolated CI from the yeast (-CI) and identify distinct closed and open states that resemble those of mammalian CI. Notably, a hitherto-unknown protein (NUQM) completes an interdomain bridge in only the closed state, implying that NUQM stabilizes it by restricting the conformational changes of opening. The direct correlation of NUQM binding with closed/open status in -CI provides opportunities for investigating regulatory mechanisms relevant to reversible catalysis and ischemia-reperfusion injury.
External linksSci Adv / PubMed:41032597 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 20.0 Å
Structure data

EMDB-52875, PDB-9iho:
Open state without NUQM and without flavoprotein (classification state 4) of Pichia pastoris mitochondrial complex I in cMSP26 nanodiscs
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-52876, PDB-9ihp:
Open state without NUQM and with flavoprotein (classification state 3) of Pichia pastoris mitochondrial complex I in cMSP26 nanodiscs
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-52877, PDB-9ihq:
Closed state with NUQM and without flavoprotein (classification state 2) of Pichia pastoris mitochondrial complex I in cMSP26 nanodiscs
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-52878, PDB-9ihr:
Closed state with NUQM and with flavoprotein (classification state 1) of Pichia pastoris mitochondrial complex I in cMSP26 nanodiscs
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-52890: NUQM-free state of Pichia pastoris mitochondrial complex I reconstituted into proteoliposomes
Method: EM (single particle) / Resolution: 8.2 Å

EMDB-52891: NUQM-bound state of Pichia pastoris mitochondrial complex I reconstituted into proteoliposomes
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-52892: Flavoprotein (NUHM and NUBM)-free state of Pichia pastoris mitochondrial complex I reconstituted into proteoliposomes
Method: EM (single particle) / Resolution: 20.0 Å

EMDB-52893: Flavoprotein (NUHM and NUBM)-containing state of Pichia pastoris mitochondrial complex I reconstituted into proteoliposomes
Method: EM (single particle) / Resolution: 4.7 Å

Chemicals

ChemComp-SF4:
IRON/SULFUR CLUSTER

ChemComp-PLC:
DIUNDECYL PHOSPHATIDYL CHOLINE / phospholipid*YM

ChemComp-K:
Unknown entry

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

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

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

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

ChemComp-FMN:
FLAVIN MONONUCLEOTIDE

Source
  • komagataella pastoris (fungus)
  • Komagataella phaffii (fungus)
KeywordsMEMBRANE PROTEIN / NADH:ubiquinone oxidoreductase nanodisc membrane protein complex

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