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Journal Article

Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion


Nolte,  H.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

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Škerlová, J., Berndtsson, J., Nolte, H., Ott, M., & Stenmark, P. (2021). Structure of the native pyruvate dehydrogenase complex reveals the mechanism of substrate insertion. Nat Commun, 12(1), 5277. doi:10.1038/s41467-021-25570-y.

Cite as: https://hdl.handle.net/21.11116/0000-000A-B7A9-9
The pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A. PDHc encompasses three enzymatically active subunits, namely pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. Dihydrolipoyl transacetylase is a multidomain protein comprising a varying number of lipoyl domains, a peripheral subunit-binding domain, and a catalytic domain. It forms the structural core of the complex, provides binding sites for the other enzymes, and shuffles reaction intermediates between the active sites through covalently bound lipoyl domains. The molecular mechanism by which this shuttling occurs has remained elusive. Here, we report a cryo-EM reconstruction of the native E. coli dihydrolipoyl transacetylase core in a resting state. This structure provides molecular details of the assembly of the core and reveals how the lipoyl domains interact with the core at the active site.