1U5B: Crystal Structure Of The Human Mitochondrial Branched-Chain Alpha- Ketoacid Dehydrogenase

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.
PDB ID: 1U5BDownload
MMDB ID: 30363
PDB Deposition Date: 2004/7/27
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.83  Å
Source Organism:
Similar Structures:
Biological Unit for 1U5B: tetrameric; determined by author and by software (PISA,PQS)
Molecular Components in 1U5B
Label Count Molecule
Proteins (4 molecules)
2-oxoisovalerate Dehydrogenase Alpha Subunit(Gene symbol: BCKDHA)
Molecule annotation
2-oxoisovalerate Dehydrogenase Beta Subunit(Gene symbol: BCKDHB)
Molecule annotation
Chemicals (10 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB