PDBsum entry 3exg

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protein metals Protein-protein interface(s) links
Oxidoreductase PDB id
Protein chains
(+ 10 more) 342 a.a. *
(+ 10 more) 329 a.a. *
__K ×16
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Crystal structure of the pyruvate dehydrogenase (e1p) compon human pyruvate dehydrogenase complex
Structure: Pyruvate dehydrogenase e1 component subunit alpha form, mitochondrial. Chain: a, c, e, g, i, k, m, o, q, s, u, w, y, 1, 3, 5. Fragment: e1p-alpha. Synonym: pyruvate dehydrogenase (e1p) alpha subunit. Pdhe1- engineered: yes. Mutation: yes. Other_details: phosphorylation site 1 (s264) only mutant (s203a/s271a) with the site 1 being phosphorylated. Apo for
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pdha1, phe1a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: pdhb, phe1b.
3.01Å     R-factor:   0.192     R-free:   0.253
Authors: M.Kato,R.M.Wynn,J.L.Chuang,S.-C.Tso,M.Machius,J.Li,D.T.Chuan
Key ref:
M.Kato et al. (2008). Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure, 16, 1849-1859. PubMed id: 19081061 DOI: 10.1016/j.str.2008.10.010
16-Oct-08     Release date:   25-Nov-08    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P08559  (ODPA_HUMAN) -  Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial
390 a.a.
342 a.a.*
Protein chains
Pfam   ArchSchema ?
P11177  (ODPB_HUMAN) -  Pyruvate dehydrogenase E1 component subunit beta, mitochondrial
359 a.a.
329 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, 1, 2, 3, 4, 5, 6: E.C.  - Pyruvate dehydrogenase (acetyl-transferring).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Oxo-acid dehydrogenase complexes
      Reaction: Pyruvate + [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine = [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + CO2
+ [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine
= [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine
+ CO(2)
      Cofactor: Thiamine diphosphate
Thiamine diphosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   6 terms 
  Biological process     metabolic process   11 terms 
  Biochemical function     catalytic activity     6 terms  


DOI no: 10.1016/j.str.2008.10.010 Structure 16:1849-1859 (2008)
PubMed id: 19081061  
Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.
M.Kato, R.M.Wynn, J.L.Chuang, S.C.Tso, M.Machius, J.Li, D.T.Chuang.
We report the crystal structures of the phosporylated pyruvate dehydrogenase (E1p) component of the human pyruvate dehydrogenase complex (PDC). The complete phosphorylation at Ser264-alpha (site 1) of a variant E1p protein was achieved using robust pyruvate dehydrogenase kinase 4 free of the PDC core. We show that unlike its unmodified counterpart, the presence of a phosphoryl group at Ser264-alpha prevents the cofactor thiamine diphosphate-induced ordering of the two loops carrying the three phosphorylation sites. The disordering of these phosphorylation loops is caused by a previously unrecognized steric clash between the phosphoryl group at site 1 and a nearby Ser266-alpha, which nullifies a hydrogen-bonding network essential for maintaining the loop conformations. The disordered phosphorylation loops impede the binding of lipoyl domains of the PDC core to E1p, negating the reductive acetylation step. This results in the disruption of the substrate channeling in the PDC, leading to the inactivation of this catalytic machine.
  Selected figure(s)  
Figure 4.
Figure 4. Hydrogen-Bond Networks Involving Phosphorylation Site 1
(A) The H-bond network connecting phosphorylation site 1 and Tyr33-β′ of the E1p-β′ subunit in the wild-type E1p structure. Ph-loop A is in orange, and Ph-loop B in yellow. The positions of the three phosphorylation sites are shown as spheres at the corresponding Cα atom positions. Water molecules are depicted as small red spheres. H-bonds are indicated by gray dashed lines.
(B) A similar H-bond network in the Ser264E-α mutant E1p structure (PDB ID code 2OZL; Seifert et al., 2007).
(C) A stereo diagram showing absence of the H-bond network in phospho-S1-E1p containing bound Mn-ThDP. The phosphoryl group on Ser264-α (site 1) clashes with the side chain of the neighboring Ser266-α. Van der Waals radii of the phosphoryl group and side chains of both serine residues are shown as spheres of red dots.
(D) A stereo figure of the 2Fo-Fc electron density map (contoured at 1σ) at phosphorylation site 1 with a stick representation of the refined model.
(E) Average B-factor plots of the wild-type and phospho-S1-E1p structures. Average B-factors for individual residues in one of the four nonphosphorylated wild-type E1p-α subunits (solid line) and one of the two phospho-S1-E1p-α subunits with the wild-type-like “ordered” Ph-loops (dashed line) are plotted against the residue number.
The residue ranges for Ph-loops A and B are indicated on top of the graph. Each of the three phosphorylation sites and residue Ser266-α are labeled.
Figure 5.
Figure 5. Extensive Interactions between the Two Ph-Loops in the Wild-Type E1p Structure
The stereo diagram illustrates extensive interactions between Ph-loop A (orange) and Ph-loop B (yellow) in the nonphosphorylated wild-type E1p structure. The Ph-loops are shown as stick models. Side chains of some residues are omitted for clarity. The three phosphorylation sites are S264-α (site 1), S271-α (site 2), and S203-α (site 3). Water molecules are shown as small red spheres, and the manganese atom as a pink sphere. H-bonds are indicated by gray lines.
  The above figures are reprinted by permission from Cell Press: Structure (2008, 16, 1849-1859) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21318135 T.A.Hirani, A.Tovar-Méndez, J.A.Miernyk, and D.D.Randall (2011).
Asp295 stabilizes the active-site loop structure of pyruvate dehydrogenase, facilitating phosphorylation of ser292 by pyruvate dehydrogenase-kinase.
  Enzyme Res, 2011, 939068.  
20213668 R.J.Falconer, A.Penkova, I.Jelesarov, and B.M.Collins (2010).
Survey of the year 2008: applications of isothermal titration calorimetry.
  J Mol Recognit, 23, 395-413.  
19240034 C.A.Brautigam, R.M.Wynn, J.L.Chuang, and D.T.Chuang (2009).
Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex.
  J Biol Chem, 284, 13086-13098.  
19833728 J.Li, M.Kato, and D.T.Chuang (2009).
Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate.
  J Biol Chem, 284, 34458-34467.  
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.