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PDBsum entry 1gz4

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1gz4
Jmol
Contents
Protein chain
551 a.a. *
Ligands
ATP ×8
TTN ×4
FUM ×4
Metals
_MN ×4
Waters ×572
* Residue conservation analysis
PDB id:
1gz4
Name: Oxidoreductase
Title: Molecular mechanism of the regulation of human mitochondrial NAD(p)+-dependent malic enzyme by atp and fumarate
Structure: NAD-dependent malic enzyme. Chain: a, b, c, d. Synonym: human mitochondrial NAD(p)+-dependent malic enzyme, NAD-me, malic enzyme 2. Ec: 1.1.1.40
Source: Homo sapiens. Human. Organism_taxid: 9606. Organelle: mitochondrion
Biol. unit: Tetramer (from PDB file)
Resolution:
2.20Å     R-factor:   0.209     R-free:   0.245
Authors: Z.Yang,C.W.Lanks,L.Tong
Key ref:
Z.Yang et al. (2002). Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate. Structure, 10, 951-960. PubMed id: 12121650 DOI: 10.1016/S0969-2126(02)00788-8
Date:
15-May-02     Release date:   25-Jul-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23368  (MAOM_HUMAN) -  NAD-dependent malic enzyme, mitochondrial
Seq:
Struc:
 
Seq:
Struc:
584 a.a.
551 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.1.1.38  - Malate dehydrogenase (oxaloacetate-decarboxylating).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. (S)-malate + NAD+ = pyruvate + CO2 + NADH
2. Oxaloacetate = pyruvate + CO2
(S)-malate
Bound ligand (Het Group name = FUM)
matches with 88.89% similarity
+
NAD(+)
Bound ligand (Het Group name = ATP)
matches with 56.25% similarity
=
pyruvate
Bound ligand (Het Group name = TTN)
matches with 75.00% similarity
+ CO(2)
+ NADH
Oxaloacetate
= pyruvate
+ CO(2)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular membrane-bounded organelle   3 terms 
  Biological process     metabolic process   3 terms 
  Biochemical function     catalytic activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(02)00788-8 Structure 10:951-960 (2002)
PubMed id: 12121650  
 
 
Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate.
Z.Yang, C.W.Lanks, L.Tong.
 
  ABSTRACT  
 
The regulation of human mitochondrial NAD(P)+-dependent malic enzyme (m-NAD-ME) by ATP and fumarate may be crucial for the metabolism of glutamine for energy production in rapidly proliferating tissues and tumors. Here we report the crystal structure at 2.2 A resolution of m-NAD-ME in complex with ATP, Mn2+, tartronate, and fumarate. Our structural, kinetic, and mutagenesis studies reveal unexpectedly that ATP is an active-site inhibitor of the enzyme, despite the presence of an exo binding site. The structure also reveals the allosteric binding site for fumarate in the dimer interface. Mutations in this binding site abolished the activating effects of fumarate. Comparison to the structure in the absence of fumarate indicates a possible molecular mechanism for the allosteric function of this compound.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Structure of Human m-NAD-ME in Complex with ATP, Tartronate, Mn2+, and Fumarate(A) Schematic drawing of the monomer of human m-NAD-ME. b strands, cyan; a helices, yellow; connecting loops, purple. The two ATP molecules, tartronate (labeled T), and fumarate are shown as stick models, colored in gray for carbon atoms. The Mn2+ ion and its liganding water are shown as pink and red spheres, respectively.(B) Schematic drawing of the tetramer of the enzyme. The monomers are colored in cyan, green, yellow and purple, respectively. The fumarate molecules are in the dimer interface (labeled F). Produced with Ribbons [30].
 
  The above figure is reprinted by permission from Cell Press: Structure (2002, 10, 951-960) copyright 2002.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20839295 C.J.Illingworth, P.D.Scott, K.E.Parkes, C.R.Snell, M.P.Campbell, and C.A.Reynolds (2010).
Connectivity and binding-site recognition: applications relevant to drug design.
  J Comput Chem, 31, 2677-2688.  
19091740 J.Y.Hsieh, and H.C.Hung (2009).
Engineering of the Cofactor Specificities and Isoform-specific Inhibition of Malic Enzyme.
  J Biol Chem, 284, 4536-4544.  
19236308 J.Y.Hsieh, J.H.Liu, Y.W.Fang, and H.C.Hung (2009).
Dual roles of Lys(57) at the dimer interface of human mitochondrial NAD(P)+-dependent malic enzyme.
  Biochem J, 420, 201-209.  
19416979 J.Y.Hsieh, S.H.Chen, and H.C.Hung (2009).
Functional roles of the tetramer organization of malic enzyme.
  J Biol Chem, 284, 18096-18105.  
19725876 M.C.Gerrard Wheeler, C.L.Arias, V.G.Maurino, C.S.Andreo, and M.F.Drincovich (2009).
Identification of domains involved in the allosteric regulation of cytosolic Arabidopsis thaliana NADP-malic enzymes.
  FEBS J, 276, 5665-5677.  
18959763 J.Y.Hsieh, G.Y.Liu, and H.C.Hung (2008).
Influential factor contributing to the isoform-specific inhibition by ATP of human mitochondrial NAD(P)+-dependent malic enzyme: functional roles of the nucleotide binding site Lys346.
  FEBS J, 275, 5383-5392.  
18288573 M.C.Wheeler, C.L.Arias, M.A.Tronconi, V.G.Maurino, C.S.Andreo, and M.F.Drincovitch (2008).
Arabidopsis thaliana NADP-malic enzyme isoforms: high degree of identity but clearly distinct properties.
  Plant Mol Biol, 67, 231-242.  
17258816 B.D.Lee, C.Walss-Bass, P.M.Thompson, A.Dassori, P.A.Montero, R.Medina, S.Contreras, R.Armas, M.Ramirez, M.Pereira, R.Salazar, R.J.Leach, P.Quezada, H.Raventos, and M.A.Escamilla (2007).
Malic enzyme 2 and susceptibility to psychosis and mania.
  Psychiatry Res, 150, 1.  
17150960 E.Detarsio, C.E.Alvarez, M.Saigo, C.S.Andreo, and M.F.Drincovich (2007).
Identification of domains involved in tetramerization and malate inhibition of maize C4-NADP-malic enzyme.
  J Biol Chem, 282, 6053-6060.  
17704184 H.C.Chang, L.Y.Chen, Y.H.Lu, M.Y.Li, Y.H.Chen, C.H.Lin, and G.G.Chang (2007).
Metal ions stabilize a dimeric molten globule state between the open and closed forms of malic enzyme.
  Biophys J, 93, 3977-3988.  
16757477 J.Y.Hsieh, G.Y.Liu, G.G.Chang, and H.C.Hung (2006).
Determinants of the dual cofactor specificity and substrate cooperativity of the human mitochondrial NAD(P)+-dependent malic enzyme: functional roles of glutamine 362.
  J Biol Chem, 281, 23237-23245.  
14747989 C.W.Kuo, H.C.Hung, L.Tong, and G.G.Chang (2004).
Metal-Induced reversible structural interconversion of human mitochondrial NAD(P)+-dependent malic enzyme.
  Proteins, 54, 404-411.  
15501681 N.J.Marianayagam, M.Sunde, and J.M.Matthews (2004).
The power of two: protein dimerization in biology.
  Trends Biochem Sci, 29, 618-625.  
14596586 G.G.Chang, and L.Tong (2003).
Structure and function of malic enzymes, a new class of oxidative decarboxylases.
  Biochemistry, 42, 12721-12733.  
12853453 G.S.Rao, D.E.Coleman, W.E.Karsten, P.F.Cook, and B.G.Harris (2003).
Crystallographic studies on Ascaris suum NAD-malic enzyme bound to reduced cofactor and identification of an effector site.
  J Biol Chem, 278, 38051-38058.
PDB code: 1o0s
12962632 X.Tao, Z.Yang, and L.Tong (2003).
Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism.
  Structure, 11, 1141-1150.
PDB codes: 1pj2 1pj3 1pj4
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 code is shown on the right.