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1x80
From Proteopedia
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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
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Maple syrup urine disease, type Ia OMIM:[608348], Maple syrup urine disease, type Ib OMIM:[248611]
About this Structure
1X80 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Mar 20 15:06:12 2008
Categories: 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
