PDBsum entry 1x7y

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
Protein chains
369 a.a. *
329 a.a. *
__K ×2
Waters ×723
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of the human mitochondrial branched-chain ketoacid dehydrogenase
Structure: 2-oxoisovalerate dehydrogenase alpha subunit. Chain: a. Synonym: branched-chain alpha-keto acid dehydrogenase e1 co alpha chain, bckdh e1-alpha, bckde1a. Engineered: yes. Mutation: yes. 2-oxoisovalerate dehydrogenase beta subunit. Chain: b. Synonym: branched-chain alpha-keto acid dehydrogenase e1 co
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bckdha. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Gene: bckdhb.
Biol. unit: Tetramer (from PDB file)
1.57Å     R-factor:   0.150     R-free:   0.167
Authors: R.M.Wynn,M.Kato,M.Machius,J.L.Chuang,J.Li,D.R.Tomchick,D.T.C
Key ref:
R.M.Wynn et al. (2004). Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation. Structure, 12, 2185-2196. PubMed id: 15576032 DOI: 10.1016/j.str.2004.09.013
16-Aug-04     Release date:   23-Nov-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P12694  (ODBA_HUMAN) -  2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial
445 a.a.
369 a.a.
Protein chain
Pfam   ArchSchema ?
P21953  (ODBB_HUMAN) -  2-oxoisovalerate dehydrogenase subunit beta, mitochondrial
392 a.a.
329 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Oxo-acid dehydrogenase complexes
      Reaction: 3-methyl-2-oxobutanoate + [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] lipoyllysine = [dihydrolipoyllysine- residue (2-methylpropanoyl)transferase] S-(2-methylpropanoyl)dihydrolipoyllysine + CO2
Bound ligand (Het Group name = GOL)
matches with 55.56% similarity
+ [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] lipoyllysine
= [dihydrolipoyllysine- residue (2-methylpropanoyl)transferase] S-(2-methylpropanoyl)dihydrolipoyllysine
+ CO(2)
      Cofactor: Thiamine diphosphate
Thiamine diphosphate
Bound ligand (Het Group name = TDP) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     mitochondrion   3 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     8 terms  


DOI no: 10.1016/j.str.2004.09.013 Structure 12:2185-2196 (2004)
PubMed id: 15576032  
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.
R.M.Wynn, M.Kato, M.Machius, J.L.Chuang, J.Li, D.R.Tomchick, D.T.Chuang.
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.
  Selected figure(s)  
Figure 6.
Figure 6. Predicted Steric Clashes in Phosphorylated, S292E-a, and S292Q-a E1b Structures(A-D) In the (A) phosphorylated, (B) S292E-a, (C) S292N-a, and (D) S292Q-a structures, modeled van der Waals surfaces for the phosphoryl group or substituted residues, which predict steric clashes with His291-a, except Asn292-a, are based on coordinates of the wild-type structure in Figure 5A. These steric clashes result in the destabilization of the hydrogen bond network and therefore disorder the loop. Conformations for ThDP, Arg114-a, and the Cl - ion that coordinates to the 4' amino group on the aminopyrimidine ring of ThDP, His146-b', and Tyr113-a are derived from 2F[o] - F[c] electron densities.
  The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 2185-2196) copyright 2004.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19858196 M.M.Islam, M.Nautiyal, R.M.Wynn, J.A.Mobley, D.T.Chuang, and S.M.Hutson (2010).
Branched-chain amino acid metabolon: interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm).
  J Biol Chem, 285, 265-276.  
19801660 S.Kale, and F.Jordan (2009).
Conformational ensemble modulates cooperativity in the rate-determining catalytic step in the E1 component of the Escherichia coli pyruvate dehydrogenase multienzyme complex.
  J Biol Chem, 284, 33122-33129.  
18385140 M.J.Rardin, S.E.Wiley, A.N.Murphy, D.J.Pagliarini, and J.E.Dixon (2008).
Dual specificity phosphatases 18 and 21 target to opposing sides of the mitochondrial inner membrane.
  J Biol Chem, 283, 15440-15450.  
19081061 M.Kato, R.M.Wynn, J.L.Chuang, S.C.Tso, M.Machius, J.Li, and D.T.Chuang (2008).
Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.
  Structure, 16, 1849-1859.
PDB codes: 3exe 3exf 3exg 3exh 3exi
18767075 N.Bisek, S.Wetzel, H.D.Arndt, and H.Waldmann (2008).
Synthesis and conformational analysis of stevastelin C3 analogues and their activity against the dual-specific vaccina H1-related phosphatase.
  Chemistry, 14, 8847-8860.  
17329260 J.Li, M.Machius, J.L.Chuang, R.M.Wynn, and D.T.Chuang (2007).
The two active sites in human branched-chain alpha-keto acid dehydrogenase operate independently without an obligatory alternating-site mechanism.
  J Biol Chem, 282, 11904-11913.
PDB code: 2j9f
17314104 M.M.Islam, R.Wallin, R.M.Wynn, M.Conway, H.Fujii, J.A.Mobley, D.T.Chuang, and S.M.Hutson (2007).
A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex.
  J Biol Chem, 282, 11893-11903.  
16337125 D.J.Pagliarini, and J.E.Dixon (2006).
Mitochondrial modulation: reversible phosphorylation takes center stage?
  Trends Biochem Sci, 31, 26-34.  
16436377 L.G.Korotchkina, S.Sidhu, and M.S.Patel (2006).
Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase.
  J Biol Chem, 281, 9688-9696.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.