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PDBsum entry 1p1v

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1p1v
Jmol
Contents
Protein chain
146 a.a. *
Ligands
SO4 ×3
Metals
_ZN ×6
Waters ×736
* Residue conservation analysis
PDB id:
1p1v
Name: Oxidoreductase
Title: Crystal structure of fals-associated human copper-zinc superoxide dismutase (cuznsod) mutant d125h to 1.4a
Structure: Superoxide dismutase [cu-zn]. Chain: a, b, c. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.
Biol. unit: Dimer (from PDB file)
Resolution:
1.40Å     R-factor:   0.147     R-free:   0.212
Authors: J.S.Elam,K.Malek,J.A.Rodriguez,P.A.Doucette,A.B.Taylor, L.J.Hayward,D.E.Cabelli,J.S.Valentine,P.J.Hart
Key ref:
J.S.Elam et al. (2003). An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate. J Biol Chem, 278, 21032-21039. PubMed id: 12649272 DOI: 10.1074/jbc.M300484200
Date:
14-Apr-03     Release date:   26-Aug-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
Seq:
Struc:
154 a.a.
146 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.15.1.1  - Superoxide dismutase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 superoxide + 2 H+ = O2 + H2O2
2 × superoxide
+ 2 × H(+)
= O(2)
+ H(2)O(2)
      Cofactor: Fe cation or Mn(2+) or (Zn(2+) and Cu cation)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   20 terms 
  Biological process     cellular response to potassium ion   66 terms 
  Biochemical function     antioxidant activity     13 terms  

 

 
    Added reference    
 
 
DOI no: 10.1074/jbc.M300484200 J Biol Chem 278:21032-21039 (2003)
PubMed id: 12649272  
 
 
An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate.
J.S.Elam, K.Malek, J.A.Rodriguez, P.A.Doucette, A.B.Taylor, L.J.Hayward, D.E.Cabelli, J.S.Valentine, P.J.Hart.
 
  ABSTRACT  
 
Hydrogen peroxide can interact with the active site of copper-zinc superoxide dismutase (SOD1) to generate a powerful oxidant. This oxidant can either damage amino acid residues at the active site, inactivating the enzyme (the self-oxidative pathway), or oxidize substrates exogenous to the active site, preventing inactivation (the external oxidative pathway). It is well established that the presence of bicarbonate anion dramatically enhances the rate of oxidation of exogenous substrates. Here, we show that bicarbonate also substantially enhances the rate of self-inactivation of human wild type SOD1. Together, these observations suggest that the strong oxidant formed by hydrogen peroxide and SOD1 in the presence of bicarbonate arises from a pathway mechanistically distinct from that producing the oxidant in its absence. Self-inactivation rates are further enhanced in a mutant SOD1 protein (L38V) linked to the fatal neurodegenerative disorder, familial amyotrophic lateral sclerosis. The 1.4 A resolution crystal structure of pathogenic SOD1 mutant D125H reveals the mode of oxyanion binding in the active site channel and implies that phosphate anion attenuates the bicarbonate effect by competing for binding to this site. The orientation of the enzyme-associated oxyanion suggests that both the self-oxidative and external oxidative pathways can proceed through an enzyme-associated peroxycarbonate intermediate.
 
  Selected figure(s)  
 
Figure 2.
FIG. 2. X-ray crystal structure of the copper-binding site of FALS SOD1 mutant D125H. A, the active site of one monomer of D125H is superimposed on 1.4 Å electron density with coefficients 2mF[o] - DF[c] contoured at 1.3 . The histidine copper ligands and zinc ions are labeled. A sulfate anion (green and yellow, all of the oxygen atoms with the exception of the one designated with a red asterisk) is found associated with Arg-143 in the anion-binding site and is bound to the zinc ion through its OX1 atom. Bicarbonate anion (yellow, OX1, OX2, and oxygen labeled with the red asterisk) is modeled based on the position of the sulfate anion (see "Experimental Procedures"). The side chain of Asn-26 (green) comes from a symmetry-related molecule in the crystal lattice and hydrogen bonds simultaneously to the OX2 atom of the oxyanion and to the carbonyl oxygen atom of Gly-141. B, space-filling model of the D125H active site with bound bicarbonate when viewed from the solvent. D125H carbon and oxygen atoms are shown in gray, and nitrogen atoms are shown in blue. The carbon atoms of Arg-143 and Thr-137, residues forming the active site channel constriction, are shown in pink. The positive charge on the guanidinium group of Arg-143 is represented by a (+) symbol. Residues known to be oxidatively damaged in the active site through mass spectrometry analyses (13, 14) are shown in light green. The C 1 position of His-120 is indicated (see "Discussion"). The zinc ion is shown in yellow. The carbonate oxygen atoms are labeled OX2 and OX3 (red), and its carbon atom is shown in black.
Figure 3.
FIG. 3. Proposed mechanism for bicarbonate-mediated peroxidation in SOD1 (see "Discussion"). i, Cu(II) is reduced to Cu(I). ii, bicarbonate binds to the anion-binding site in the manner predicted by the D125H SOD1 crystal structure. iii, reacts with bicarbonate to form peroxycarbonate (iv). v, the oxygen radical species formed [O*] may then oxidize endogenous or exogenous substrates, leaving bicarbonate bound to the anion-binding site (vi). B, the attack of an oxygen radical species on one of the histidine copper ligands in SOD1 leads to the formation of a 2-oxo histidine adduct, leading to cofactor loss and enzyme inactivation.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 21032-21039) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20030376 D.T.Houghton, N.W.Gydesen, N.Arulsamy, and M.P.Mehn (2010).
Synthesis and characterization of iron(II) quinaldate complexes.
  Inorg Chem, 49, 879-887.  
20133726 L.Goldschmidt, P.K.Teng, R.Riek, and D.Eisenberg (2010).
Identifying the amylome, proteins capable of forming amyloid-like fibrils.
  Proc Natl Acad Sci U S A, 107, 3487-3492.  
20232802 R.J.Nowak, G.D.Cuny, S.Choi, P.T.Lansbury, and S.S.Ray (2010).
Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods.
  J Med Chem, 53, 2709-2718.  
19651777 A.Tiwari, A.Liba, S.H.Sohn, S.V.Seetharaman, O.Bilsel, C.R.Matthews, P.J.Hart, J.S.Valentine, and L.J.Hayward (2009).
Metal deficiency increases aberrant hydrophobicity of mutant superoxide dismutases that cause amyotrophic lateral sclerosis.
  J Biol Chem, 284, 27746-27758.  
18764780 D.C.Ramirez, S.E.Gomez-Mejiba, J.T.Corbett, L.J.Deterding, K.B.Tomer, and R.P.Mason (2009).
Cu,Zn-superoxide dismutase-driven free radical modifications: copper- and carbonate radical anion-initiated protein radical chemistry.
  Biochem J, 417, 341-353.  
19635794 K.S.Molnar, N.M.Karabacak, J.L.Johnson, Q.Wang, A.Tiwari, L.J.Hayward, S.J.Coales, Y.Hamuro, and J.N.Agar (2009).
A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop.
  J Biol Chem, 284, 30965-30973.  
19462668 L.F.Barbosa, C.C.Garcia, P.Di Mascio, and M.H.de Medeiros (2009).
DNA oxidation, strand-breaks and etheno-adducts formation promoted by Cu, Zn-superoxide dismutase-H2O2 in the presence and absence of bicarbonate.
  Dalton Trans, (), 1450-1459.  
19286663 M.G.Bonini, S.A.Gabel, K.Ranguelova, K.Stadler, E.F.Derose, R.E.London, and R.P.Mason (2009).
Direct magnetic resonance evidence for peroxymonocarbonate involvement in the cu,zn-superoxide dismutase peroxidase catalytic cycle.
  J Biol Chem, 284, 14618-14627.  
19421792 Q.Lu, X.Li, Y.Wang, and G.Chen (2009).
Catalytic activities of dismution reactions of Cu(bpy)Br(2) compound and its derivatives as SOD mimics: a theoretical study.
  J Mol Model, 15, 1397-1405.  
19596823 S.V.Seetharaman, M.Prudencio, C.Karch, S.P.Holloway, D.R.Borchelt, and P.J.Hart (2009).
Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.
  Exp Biol Med (Maywood), 234, 1140-1154.  
18192269 B.F.Shaw, H.L.Lelie, A.Durazo, A.M.Nersissian, G.Xu, P.K.Chan, E.B.Gralla, A.Tiwari, L.J.Hayward, D.R.Borchelt, J.S.Valentine, and J.P.Whitelegge (2008).
Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1.
  J Biol Chem, 283, 8340-8350.  
18370853 M.Cozzolino, A.Ferri, and M.T.Carrì (2008).
Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications.
  Antioxid Redox Signal, 10, 405-443.  
18378676 X.Cao, S.V.Antonyuk, S.V.Seetharaman, L.J.Whitson, A.B.Taylor, S.P.Holloway, R.W.Strange, P.A.Doucette, J.S.Valentine, A.Tiwari, L.J.Hayward, S.Padua, J.A.Cohlberg, S.S.Hasnain, and P.J.Hart (2008).
Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis.
  J Biol Chem, 283, 16169-16177.
PDB codes: 2vr6 2vr7 2vr8 3cqp 3cqq
17888947 B.R.Roberts, J.A.Tainer, E.D.Getzoff, D.A.Malencik, S.R.Anderson, V.C.Bomben, K.R.Meyers, P.A.Karplus, and J.S.Beckman (2007).
Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS.
  J Mol Biol, 373, 877-890.
PDB code: 2r27
17048125 O.Augusto, and S.Muntz Vaz (2007).
EPR spin-trapping of protein radicals to investigate biological oxidative mechanisms.
  Amino Acids, 32, 535-542.  
17548825 R.W.Strange, C.W.Yong, W.Smith, and S.S.Hasnain (2007).
Molecular dynamics using atomic-resolution structure reveal structural fluctuations that may lead to polymerization of human Cu-Zn superoxide dismutase.
  Proc Natl Acad Sci U S A, 104, 10040-10044.
PDB code: 2v0a
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.  
16516535 P.J.Hart (2006).
Pathogenic superoxide dismutase structure, folding, aggregation and turnover.
  Curr Opin Chem Biol, 10, 131-138.  
16804677 W.Jiang, T.Shen, Y.Han, Q.Pan, and C.Liu (2006).
Divalent-metal-dependent nucleolytic activity of Cu, Zn superoxide dismutase.
  J Biol Inorg Chem, 11, 835-848.  
15880490 D.S.Webber, I.Lopez, R.A.Korsak, S.Hirota, D.Acuna, and J.Edmond (2005).
Limiting iron availability confers neuroprotection from chronic mild carbon monoxide exposure in the developing auditory system of the rat.
  J Neurosci Res, 80, 620-633.  
16027354 H.Arai, B.S.Berlett, P.B.Chock, and E.R.Stadtman (2005).
Effect of bicarbonate on iron-mediated oxidation of low-density lipoprotein.
  Proc Natl Acad Sci U S A, 102, 10472-10477.  
16020530 J.A.Rodriguez, B.F.Shaw, A.Durazo, S.H.Sohn, P.A.Doucette, A.M.Nersissian, K.F.Faull, D.K.Eggers, A.Tiwari, L.J.Hayward, and J.S.Valentine (2005).
Destabilization of apoprotein is insufficient to explain Cu,Zn-superoxide dismutase-linked ALS pathogenesis.
  Proc Natl Acad Sci U S A, 102, 10516-10521.  
15952898 J.S.Valentine, P.A.Doucette, and S.Zittin Potter (2005).
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.
  Annu Rev Biochem, 74, 563-593.  
15840828 S.Antonyuk, J.S.Elam, M.A.Hough, R.W.Strange, P.A.Doucette, J.A.Rodriguez, L.J.Hayward, J.S.Valentine, P.J.Hart, and S.S.Hasnain (2005).
Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg.
  Protein Sci, 14, 1201-1213.  
15062777 A.F.Miller (2004).
Superoxide dismutases: active sites that save, but a protein that kills.
  Curr Opin Chem Biol, 8, 162-168.  
15056757 M.A.Hough, J.G.Grossmann, S.V.Antonyuk, R.W.Strange, P.A.Doucette, J.A.Rodriguez, L.J.Whitson, P.J.Hart, L.J.Hayward, J.S.Valentine, and S.S.Hasnain (2004).
Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.
  Proc Natl Acad Sci U S A, 101, 5976-5981.
PDB codes: 1uxl 1uxm
15122650 M.Davydova, R.Sabirova, N.Vylegzhanina, and N.Tarasova (2004).
Carbon monoxide and oxidative stress in Desulfovibrio desulfuricans B-1388.
  J Biochem Mol Toxicol, 18, 87-91.  
14711995 S.I.Liochev, and I.Fridovich (2004).
CO2, not HCO3-, facilitates oxidations by Cu,Zn superoxide dismutase plus H2O2.
  Proc Natl Acad Sci U S A, 101, 743-744.  
15135181 S.I.Liochev, and I.Fridovich (2004).
CO2 enhanced peroxidase activity of SOD1: the effects of pH.
  Free Radic Biol Med, 36, 1444-1447.  
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.