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PDBsum entry 1ni4

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1ni4
Jmol
Contents
Protein chains
362 a.a. *
330 a.a. *
Ligands
TPP ×2
Metals
__K ×2
_MG ×2
Waters ×742
* Residue conservation analysis
PDB id:
1ni4
Name: Oxidoreductase
Title: Human pyruvate dehydrogenase
Structure: Pyruvate dehydrogenase e1 component: alpha subunit. Chain: a, c. Synonym: pdhe1-a type i. Engineered: yes. Pyruvate dehydrogenase e1 component: beta subunit. Chain: b, d. Synonym: pdhe1-b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
1.95Å     R-factor:   0.202     R-free:   0.244
Authors: E.Ciszak,L.G.Korotchkina,P.M.Dominiak,S.Sidhu,M.S.Patel
Key ref:
E.M.Ciszak et al. (2003). Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase. J Biol Chem, 278, 21240-21246. PubMed id: 12651851 DOI: 10.1074/jbc.M300339200
Date:
20-Dec-02     Release date:   17-Jun-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P08559  (ODPA_HUMAN) -  Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial
Seq:
Struc:
390 a.a.
362 a.a.*
Protein chains
Pfam   ArchSchema ?
P11177  (ODPB_HUMAN) -  Pyruvate dehydrogenase E1 component subunit beta, mitochondrial
Seq:
Struc:
359 a.a.
330 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.1.2.4.1  - Pyruvate dehydrogenase (acetyl-transferring).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Oxo-acid dehydrogenase complexes
      Reaction: Pyruvate + [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine = [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + CO2
Pyruvate
+ [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine
= [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine
+ CO(2)
      Cofactor: Thiamine diphosphate
Thiamine diphosphate
Bound ligand (Het Group name = TPP) corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular vesicular exosome   7 terms 
  Biological process     metabolic process   11 terms 
  Biochemical function     catalytic activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M300339200 J Biol Chem 278:21240-21246 (2003)
PubMed id: 12651851  
 
 
Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase.
E.M.Ciszak, L.G.Korotchkina, P.M.Dominiak, S.Sidhu, M.S.Patel.
 
  ABSTRACT  
 
The derivative of vitamin B1, thiamin pyrophosphate, is a cofactor of enzymes performing catalysis in pathways of energy production. In alpha2beta2-heterotetrameric human pyruvate dehydrogenase, this cofactor is used to cleave the Calpha-C(=O) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites has not yet been understood. To understand the mechanism of action of this enzyme, we determined the crystal structure of the holo-form of human pyruvate dehydrogenase at 1.95-A resolution. We propose a model for the flip-flop action of this enzyme through a concerted approximately 2-A shuttle-like motion of its heterodimers. Similarity of thiamin pyrophosphate binding in human pyruvate dehydrogenase with functionally related enzymes suggests that this newly defined shuttle-like motion of domains is common to the family of thiamin pyrophosphate-dependent enzymes.
 
  Selected figure(s)  
 
Figure 2.
FIG. 2. Structure of human pyruvate dehydrogenase (E1p). The four subunits are arranged tetrahedrally as shown in the following colors: , red; ', green; , yellow; and ', blue. The molecule possesses a 2-fold symmetry axis that relates the with the ' subunit and with the ' subunit. Two cofactor molecules, TPP, are shown in black. Two Mg2+ ions, each at the pyrophosphate terminus of TPP, are shown as spheres in dark blue. The two K+ ions contained in the structure are represented as magenta spheres. The locations of six domains termed PP, PP', PYR, PYR', C, and C' domains distributed along the alpha and beta subunits are indicated by arrows. This figure was prepared using PyMol (33).
Figure 3.
FIG. 3. K+ binding site in E1p. The metal binding at this site stabilizes the negative end of the helix (160-165) in the PYR domain of the subunit that forms interactions with the C terminus of the subunit (340-343 and 361). The coordination of K+ is maintained by four carbonyl oxygen atoms, three from Ala^160, Asp163, Asn165, and one from Ile^112. There, coordination is completed by the water molecule W10 to form geometry of a distorted tetragonal pyramid. Similar contacts are observed between the second K+ ion and the symmetry-related ' and ' subunits.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 21240-21246) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21983965 J.Du, R.F.Say, W.Lü, G.Fuchs, and O.Einsle (2011).
Active-site remodelling in the bifunctional fructose-1,6-bisphosphate aldolase/phosphatase.
  Nature, 478, 534-537.
PDB codes: 3t2b 3t2c 3t2d 3t2e 3t2f 3t2g
20099870 X.Y.Pei, K.M.Erixon, B.F.Luisi, and F.J.Leeper (2010).
Structural insights into the prereaction state of pyruvate decarboxylase from Zymomonas mobilis .
  Biochemistry, 49, 1727-1736.
PDB codes: 2wva 2wvg 2wvh
20160912 M.S.Patel, L.G.Korotchkina, and S.Sidhu (2009).
Interaction of E1 and E3 components with the core proteins of the human pyruvate dehydrogenase complex.
  J Mol Catal B Enzym, 61, 2-6.  
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.  
19698086 V.I.Bunik, and A.R.Fernie (2009).
Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation.
  Biochem J, 422, 405-421.  
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
18316329 T.Nakai, S.Kuramitsu, and N.Kamiya (2008).
Structural bases for the specific interactions between the E2 and E3 components of the Thermus thermophilus 2-oxo acid dehydrogenase complexes.
  J Biochem, 143, 747-758.  
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.  
18184588 X.Yu, Y.Hiromasa, H.Tsen, J.K.Stoops, T.E.Roche, and Z.H.Zhou (2008).
Structures of the human pyruvate dehydrogenase complex cores: a highly conserved catalytic center with flexible N-terminal domains.
  Structure, 16, 104-114.
PDB code: 3b8k
17391016 H.Xie, S.Vucetic, L.M.Iakoucheva, C.J.Oldfield, A.K.Dunker, Z.Obradovic, and V.N.Uversky (2007).
Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins.
  J Proteome Res, 6, 1917-1932.  
17311134 K.M.Erixon, C.L.Dabalos, and F.J.Leeper (2007).
Inhibition of pyruvate decarboxylase from Z. mobilis by novel analogues of thiamine pyrophosphate: investigating pyrophosphate mimics.
  Chem Commun (Camb), (), 960-962.  
17182735 N.Nemeria, S.Chakraborty, A.Baykal, L.G.Korotchkina, M.S.Patel, and F.Jordan (2007).
The 1',4'-iminopyrimidine tautomer of thiamin diphosphate is poised for catalysis in asymmetric active centers on enzymes.
  Proc Natl Acad Sci U S A, 104, 78-82.  
15612915 B.J.Foth, L.M.Stimmler, E.Handman, B.S.Crabb, A.N.Hodder, and G.I.McFadden (2005).
The malaria parasite Plasmodium falciparum has only one pyruvate dehydrogenase complex, which is located in the apicoplast.
  Mol Microbiol, 55, 39-53.  
15634348 M.D.Allen, R.W.Broadhurst, R.G.Solomon, and R.N.Perham (2005).
Interaction of the E2 and E3 components of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus. Use of a truncated protein domain in NMR spectroscopy.
  FEBS J, 272, 259-268.
PDB code: 1w3d
16084384 R.A.Frank, J.V.Pratap, X.Y.Pei, R.N.Perham, and B.F.Luisi (2005).
The molecular origins of specificity in the assembly of a multienzyme complex.
  Structure, 13, 1119-1130.
PDB code: 2bp7
15752351 R.Golbik, L.E.Meshalkina, T.Sandalova, K.Tittmann, E.Fiedler, H.Neef, S.König, R.Kluger, G.A.Kochetov, G.Schneider, and G.Hübner (2005).
Effect of coenzyme modification on the structural and catalytic properties of wild-type transketolase and of the variant E418A from Saccharomyces cerevisiae.
  FEBS J, 272, 1326-1342.  
15514144 F.Jordan (2004).
Biochemistry. How active sites communicate in thiamine enzymes.
  Science, 306, 818-820.  
15576032 R.M.Wynn, M.Kato, M.Machius, J.L.Chuang, J.Li, D.R.Tomchick, and D.T.Chuang (2004).
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation.
  Structure, 12, 2185-2196.
PDB codes: 1u5b 1x7w 1x7x 1x7y 1x7z 1x80
14675553 E.Settembre, T.P.Begley, and S.E.Ealick (2003).
Structural biology of enzymes of the thiamin biosynthesis pathway.
  Curr Opin Struct Biol, 13, 739-747.  
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.

 

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