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Structure paper

TitleStructural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
Journal, issue, pagesScience, Vol. 379, Issue 6630, Page 351-357, Year 2023
Publish dateJan 27, 2023
AuthorsHannah R Bridges / James N Blaza / Zhan Yin / Injae Chung / Michael N Pollak / Judy Hirst /
PubMed AbstractThe molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target ...The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
External linksScience / PubMed:36701435 / PubMed Central
MethodsEM (single particle)
Resolution2.17 - 3.5 Å
Structure data

EMDB-14126: Bovine complex I in the slack state at 3.5 A
Method: EM (single particle) / Resolution: 3.5 Å

14127

7qsd

EMDB-14127, PDB-7qsd:
Bovine complex I in the active state at 3.1 A
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-14128: Bovine complex I in the active state at 3.1 A (Composite map)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-14129: Bovine complex I in the active state at 3.1 A (Hydrophlic domain)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-14130: Bovine complex I in the active state at 3.1 A (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-14131: Bovine complex I in the active state at 3.1 A (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 3.4 Å

14251

7r41

EMDB-14251, PDB-7r41:
Bovine complex I in the presence of IM1761092, active class i (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14252: Bovine complex I in the presence of IM1761092, active class i (Consensus)
Method: EM (single particle) / Resolution: 2.44 Å

EMDB-14253: Bovine complex I in the presence of IM1761092, active class i (Hydophilic domain)
Method: EM (single particle) / Resolution: 2.32 Å

EMDB-14254: Bovine complex I in the presence of IM1761092, active class i (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.41 Å

EMDB-14255: Bovine complex I in the presence of IM1761092, active class i (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.51 Å

14256

7r42

EMDB-14256, PDB-7r42:
Bovine complex I in the presence of IM1761092, active class ii (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14257: Bovine complex I in the presence of IM1761092, active class ii (Consensus map)
Method: EM (single particle) / Resolution: 2.42 Å

EMDB-14258: Bovine complex I in the presence of IM1761092, active class ii (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.31 Å

EMDB-14259: Bovine complex I in the presence of IM1761092, active class ii (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.41 Å

EMDB-14260: Bovine complex I in the presence of IM1761092, active class ii (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.47 Å

14261

7r43

EMDB-14261, PDB-7r43:
Bovine complex I in the presence of IM1761092, active class iii (Composite map)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14262: Bovine complex I in the presence of IM1761092, active class iii (Consensus)
Method: EM (single particle) / Resolution: 2.61 Å

EMDB-14263: Bovine complex I in the presence of IM1761092, active class iii (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.46 Å

EMDB-14264: Bovine complex I in the presence of IM1761092, active class iii (Proximal membrane domain)
Method: EM (single particle) / Resolution: 2.58 Å

EMDB-14265: Bovine complex I in the presence of IM1761092, active class iii (Distal membrane domain)
Method: EM (single particle) / Resolution: 2.62 Å

14266

7r44

EMDB-14266, PDB-7r44:
Bovine complex I in the presence of IM1761092, active class iv (Composite map)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14267: Bovine complex I in the presence of IM1761092, active class iv (Consensus)
Method: EM (single particle) / Resolution: 2.55 Å

EMDB-14268: Bovine complex I in the presence of IM1761092, active class iv (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.41 Å

EMDB-14269: Bovine complex I in the presence of IM1761092, active class iv (Proximal membrane domain)
Method: EM (single particle) / Resolution: 2.54 Å

EMDB-14270: Bovine complex I in the presence of IM1761092, active class iv (Distal membrane domain)
Method: EM (single particle) / Resolution: 2.64 Å

14272

7r45

EMDB-14272, PDB-7r45:
Bovine complex I in the presence of IM1761092, deactive class i (Composite map)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14273: Bovine complex I in the presence of IM1761092, deactive class i (Consensus)
Method: EM (single particle) / Resolution: 2.44 Å

EMDB-14274: Bovine complex I in the presence of IM1761092, deactive class i (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14275: Bovine complex I in the presence of IM1761092, deactive class i (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.46 Å

EMDB-14276: Bovine complex I in the presence of IM1761092, deactive class i (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.47 Å

14277

7r46

EMDB-14277, PDB-7r46:
Bovine complex I in the presence of IM1761092, deactive class ii (Composite map)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14278: Bovine complex I in the presence of IM1761092, deactive class ii (Consensus)
Method: EM (single particle) / Resolution: 2.57 Å

EMDB-14279: Bovine complex I in the presence of IM1761092, deactive class ii (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.44 Å

EMDB-14280: Bovine complex I in the presence of IM1761092, deactive class ii (Proximal membrane domain)
Method: EM (single particle) / Resolution: 2.55 Å

EMDB-14281: Bovine complex I in the presence of IM1761092, deactive class ii (Distal membrane domain)
Method: EM (single particle) / Resolution: 2.61 Å

14282

7r47

EMDB-14282, PDB-7r47:
Bovine complex I in the presence of IM1761092, deactive class iii (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14283: Bovine complex I in the presence of IM1761092, deactive class iii (Consensus)
Method: EM (single particle) / Resolution: 2.31 Å

EMDB-14284: Bovine complex I in the presence of IM1761092, deactive class iii (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.17 Å

EMDB-14285: Bovine complex I in the presence of IM1761092, deactive class iii (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.29 Å

EMDB-14286: Bovine complex I in the presence of IM1761092, deactive class iii (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.34 Å

14287

7r48

EMDB-14287, PDB-7r48:
Bovine complex I in the presence of IM1761092, deactive class iv (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14288: Bovine complex I in the presence of IM1761092, deactive class iv (Consensus)
Method: EM (single particle) / Resolution: 2.34 Å

EMDB-14289: Bovine complex I in the presence of IM1761092, deactive class iv (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.19 Å

EMDB-14290: Bovine complex I in the presence of IM1761092, deactive class iv (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.34 Å

EMDB-14291: Bovine complex I in the presence of IM1761092, deactive class iv (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.38 Å

14292

7r4c

EMDB-14292, PDB-7r4c:
Bovine complex I in the presence of IM1761092, deactive class v (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14293: Bovine complex I in the presence of IM1761092, deactive class v (Consensus)
Method: EM (single particle) / Resolution: 2.38 Å

EMDB-14294: Bovine complex I in the presence of IM1761092, deactive class v (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.22 Å

EMDB-14295: Bovine complex I in the presence of IM1761092, deactive class v (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.38 Å

EMDB-14296: Bovine complex I in the presence of IM1761092, deactive class v (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.4 Å

14297

7r4d

EMDB-14297, PDB-7r4d:
Bovine complex I in the presence of IM1761092, deactive class vi (Composite map)
Method: EM (single particle) / Resolution: 2.3 Å

EMDB-14298: Bovine complex I in the presence of IM1761092, deactive class vi (Consensus)
Method: EM (single particle) / Resolution: 2.33 Å

EMDB-14299: Bovine complex I in the presence of IM1761092, deactive class vi (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.19 Å

EMDB-14300: Bovine complex I in the presence of IM1761092, deactive class vi (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.35 Å

EMDB-14301: Bovine complex I in the presence of IM1761092, deactive class vi (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.4 Å

14302

7r4f

EMDB-14302, PDB-7r4f:
Bovine complex I in the presence of IM1761092, slack class i (Composite map)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14303: Bovine complex I in the presence of IM1761092, slack class i (Consensus)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-14304: Bovine complex I in the presence of IM1761092, slack class i (Hydrophilic domain)
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-14305: Bovine complex I in the presence of IM1761092, slack class i (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.41 Å

EMDB-14306: Bovine complex I in the presence of IM1761092, slack class i (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.47 Å

14307

7r4g

EMDB-14307, PDB-7r4g:
Bovine complex I in the presence of IM1761092, slack class ii (Composite map)
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-14308: Bovine complex I in the presence of IM1761092, slack class ii (Consensus)
Method: EM (single particle) / Resolution: 2.61 Å

EMDB-14309: Bovine complex I in the presence of IM1761092, slack class ii (Hydrophillic domain)
Method: EM (single particle) / Resolution: 2.37 Å

EMDB-14310: Bovine complex I in the presence of IM1761092, slack class ii (Proximal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.62 Å

EMDB-14311: Bovine complex I in the presence of IM1761092, slack class ii (Distal hydrophobic domain)
Method: EM (single particle) / Resolution: 2.68 Å

Chemicals

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

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

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

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

ChemComp-FMN:
FLAVIN MONONUCLEOTIDE / Flavin mononucleotide

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM / Cardiolipin

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

ChemComp-MG:
Unknown entry

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-K:
Unknown entry

ChemComp-I49:
1-carbamimidoyl-3-[2-(3-chloranyl-4-iodanyl-phenyl)ethyl]guanidine

ChemComp-MYR:
MYRISTIC ACID / Myristic acid

ChemComp-HOH:
WATER / Water

Source
  • bos taurus (cattle)
  • cattle (cattle)
KeywordsOXIDOREDUCTASE / Complex I

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