PDBsum entry 2bfd

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
Jmol PyMol
Protein chains
374 a.a. *
332 a.a. *
__K ×2
Waters ×601
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Reactivity modulation of human branched-chain alpha- ketoacid dehydrogenase by an internal molecular switch
Structure: 2-oxoisovalerate dehydrogenase alpha subunit. Chain: a. Fragment: residues 46-445. 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.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Groes.
Biol. unit: Tetramer (from PDB file)
1.39Å     R-factor:   0.150     R-free:   0.170
Authors: M.Machius,R.M.Wynn,J.L.Chuang,D.R.Tomchick,C.A.Brautigam, D.
Key ref:
M.Machius et al. (2006). A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase. Structure, 14, 287-298. PubMed id: 16472748 DOI: 10.1016/j.str.2005.10.009
06-Dec-04     Release date:   16-Feb-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P12694  (ODBA_HUMAN) -  2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial
445 a.a.
374 a.a.*
Protein chain
Pfam   ArchSchema ?
P21953  (ODBB_HUMAN) -  2-oxoisovalerate dehydrogenase subunit beta, mitochondrial
392 a.a.
332 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 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 = MPD)
matches with 60.00% 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   4 terms 
  Biochemical function     catalytic activity     8 terms  


DOI no: 10.1016/j.str.2005.10.009 Structure 14:287-298 (2006)
PubMed id: 16472748  
A versatile conformational switch regulates reactivity in human branched-chain alpha-ketoacid dehydrogenase.
M.Machius, R.M.Wynn, J.L.Chuang, J.Li, R.Kluger, D.Yu, D.R.Tomchick, C.A.Brautigam, D.T.Chuang.
The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates.
  Selected figure(s)  
Figure 8.
Figure 8. Scheme of hE1b-Catalyzed Reactions Emphasizing the Role of Tyr113-a as the Central Regulatory Conformational Switch
(A) Prior to substrate binding, the side chain of Tyr113-a, the switch turn (indicated by Q112|Y113|R114), and the adjacent LBD binding region are in the S conformation.
(B) Substrate binding displaces the Tyr113-a side chain and forces it into the P conformation, where it establishes a hydrogen bond to the terminal phosphate group in the ThDP cofactor and additional interactions with the sulfur in the thiazolium ring (dashed lines). Simultaneously, the switch turn is remodeled, whereupon the adjacent LBD binding region adopts a higher-affinity state for LBD.
(C and D) After, or concomitant with, (C) decarboxylation, LBD binds to hE1b, followed by (D) the transfer of an acyl moiety, derived from the degradation of valine, leucine, or isoleucine to lipoic acid (LA).
TZ, thiazolium ring; AP, aminopyrimidine ring; B, general base.
  The above figure is reprinted by permission from Cell Press: Structure (2006, 14, 287-298) copyright 2006.  
  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.  
19411760 G.Lu, H.Sun, P.She, J.Y.Youn, S.Warburton, P.Ping, T.M.Vondriska, H.Cai, C.J.Lynch, and Y.Wang (2009).
Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells.
  J Clin Invest, 119, 1678-1687.  
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
18004749 V.I.Bunik, and D.Degtyarev (2008).
Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins.
  Proteins, 71, 874-890.  
19081062 X.Y.Pei, C.M.Titman, R.A.Frank, F.J.Leeper, and B.F.Luisi (2008).
Snapshots of catalysis in the E1 subunit of the pyruvate dehydrogenase multienzyme complex.
  Structure, 16, 1860-1872.
PDB codes: 3duf 3dv0 3dva
18084069 C.L.Berthold, D.Gocke, M.D.Wood, F.J.Leeper, M.Pohl, and G.Schneider (2007).
Structure of the branched-chain keto acid decarboxylase (KdcA) from Lactococcus lactis provides insights into the structural basis for the chemoselective and enantioselective carboligation reaction.
  Acta Crystallogr D Biol Crystallogr, 63, 1217-1224.
PDB codes: 2vbf 2vbg
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.  
17342415 V.I.Bunik, J.V.Schloss, J.T.Pinto, G.E.Gibson, and A.J.Cooper (2007).
Enzyme-catalyzed side reactions with molecular oxygen may contribute to cell signaling and neurodegenerative diseases.
  Neurochem Res, 32, 871-891.  
17905741 W.Versées, S.Spaepen, M.D.Wood, F.J.Leeper, J.Vanderleyden, and J.Steyaert (2007).
Molecular mechanism of allosteric substrate activation in a thiamine diphosphate-dependent decarboxylase.
  J Biol Chem, 282, 35269-35278.
PDB codes: 2q5j 2q5l 2q5o 2q5q
17124494 M.Kato, R.M.Wynn, J.L.Chuang, C.A.Brautigam, M.Custorio, and D.T.Chuang (2006).
A synchronized substrate-gating mechanism revealed by cubic-core structure of the bovine branched-chain alpha-ketoacid dehydrogenase complex.
  EMBO J, 25, 5983-5994.
PDB codes: 2ihw 2ii3 2ii4 2ii5
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.