1x80
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| , resolution 2.00Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , and | ||||||
| Gene: | BCKDHA (Homo sapiens), BCKDHB (Homo sapiens) | ||||||
| Activity: | 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), with EC number 1.2.4.4 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase
OverviewOverview
The human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a 4 MDa macromolecular machine comprising three catalytic components (E1b, E2b, and E3), a kinase, and a phosphatase. The BCKDC overall activity is tightly regulated by phosphorylation in response to hormonal and dietary stimuli. We report that phosphorylation of Ser292-alpha in the E1b active site channel results in an order-to-disorder transition of the conserved phosphorylation loop carrying the phosphoryl serine. The conformational change is triggered by steric clashes of the phosphoryl group with invariant His291-alpha that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-alpha does not severely impede the E1b-dependent decarboxylation of alpha-ketoacids. However, the disordered loop conformation prevents phosphorylated E1b from binding the E2b lipoyl-bearing domain, which effectively shuts off the E1b-catalyzed reductive acylation reaction and therefore completely inactivates BCKDC. This mechanism provides a paradigm for regulation of mitochondrial alpha-ketoacid dehydrogenase complexes by phosphorylation.
DiseaseDisease
Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[608348], Maple syrup urine disease, type Ib OMIM:[248611]
About this StructureAbout this Structure
1X80 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation., Wynn RM, Kato M, Machius M, Chuang JL, Li J, Tomchick DR, Chuang DT, Structure. 2004 Dec;12(12):2185-96. PMID:15576032
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- 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)
- Homo sapiens
- Protein complex
- Chuang, D T.
- Chuang, J L.
- Kato, M.
- Li, J.
- Machius, M.
- Tomchick, D R.
- Wynn, R M.
- CL
- GOL
- K
- MN
- TDP
- Acylation
- Branched-chain
- Flavoprotein
- Ketoacid dehydrogenase
- Multi-enzyme complex
- Oxidative decarboxylation maple syrup urine disease
- Oxidoreductase
- Phosphorylation
- Thiamin diphosphate