PDBsum entry 3cqq

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Oxidoreductase PDB id
Protein chains
135 a.a. *
127 a.a. *
_ZN ×3
Waters ×146
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Human sod1 g85r variant, structure ii
Structure: Superoxide dismutase [cu-zn]. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.
1.90Å     R-factor:   0.195     R-free:   0.240
Authors: X.Cao,S.Antonyuk,L.J.Whitson,A.B.Taylor,S.P.Holloway,R.W.Str P.A.Doucette,J.S.Valentine,A.Tiwari,L.J.Hayward,S.Padua, J.A.Cohlberg,S.S.Hasnain,P.J.Hart
Key ref:
X.Cao et al. (2008). Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J Biol Chem, 283, 16169-16177. PubMed id: 18378676 DOI: 10.1074/jbc.M801522200
03-Apr-08     Release date:   29-Apr-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
154 a.a.
135 a.a.*
Protein chain
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
154 a.a.
127 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.  - 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.M801522200 J Biol Chem 283:16169-16177 (2008)
PubMed id: 18378676  
Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis.
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, P.J.Hart.
Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.
  Selected figure(s)  
Figure 2.
FIGURE 2. The G85R mutation site and the copper- and zinc-binding sites. The wild type protein is shown in yellow. A, three of the four conformations observed in the 10 unique subunits of the four crystal structures are shown in light blue, green, and pink, respectively (see text). Copper and zinc ions are represented as cyan and gray spheres, respectively. The dual hydrogen bonds formed by Asp^124 to the copper ligand His^46 and the zinc ligand His^71 as well as the hydrogen bonding network between Pro^74, Arg^79, and Asp^101 are shown as dotted lines. B, the image is the same as in A except rotated 90° around the horizontal and vertical axes in the plane of the page. The electrostatic loop has been removed for clarity. C, the location of the three proline residues of the zinc loop (see text). The disulfide loop (residues 50-62), a substructure of the zinc loop, is shown in green. The remainder of the zinc loop containing the zinc-binding ligands, residues 63-83, is shown in blue. Pro^62, Pro^66, and Pro^74 in the zinc-bound conformation of the zinc loop are shown in magenta. The altered position of the five-membered ring of Pro^74 and the Arg^85 side chain are shown in orange. The hydrogen bond normally found between the carbonyl oxygen of Pro^74 and the guanidinium group of Arg^79 is disrupted. D, structural state four (see text) found in G85R subunits C, E, and F (see Table 2). The absence of electron density around the carbon and the Arg^85 side chain indicates that this residue is conformationally mobile, sampling many positions. This movement is correlated with both zinc deficiency in the zinc site and disorder of the zinc and electrostatic loop elements.
Figure 4.
FIGURE 4. A novel water molecule gains access to the active site area in the three subunits with a displaced 85-86 peptide bond (see also Table 2 and the text). The wild type enzyme is shown in yellow, and the G85R SOD1 mutant is shown in pink. The water molecule gaining access to zinc site in the G85R structure is shown as a green sphere.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 16169-16177) copyright 2008.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21098299 J.R.Auclair, K.J.Boggio, G.A.Petsko, D.Ringe, and J.N.Agar (2010).
Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis.
  Proc Natl Acad Sci U S A, 107, 21394-21399.  
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.  
19800308 A.Galaleldeen, R.W.Strange, L.J.Whitson, S.V.Antonyuk, N.Narayana, A.B.Taylor, J.P.Schuermann, S.P.Holloway, S.S.Hasnain, and P.J.Hart (2009).
Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A.
  Arch Biochem Biophys, 492, 40-47.
PDB codes: 2wko 3gzo 3gzp 3gzq
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.  
19227972 D.D.Winkler, J.P.Schuermann, X.Cao, S.P.Holloway, D.R.Borchelt, M.C.Carroll, J.B.Proescher, V.C.Culotta, and P.J.Hart (2009).
Structural and biophysical properties of the pathogenic SOD1 variant H46R/H48Q.
  Biochemistry, 48, 3436-3447.
PDB code: 3gqf
19088715 F.Chiti, and C.M.Dobson (2009).
Amyloid formation by globular proteins under native conditions.
  Nat Chem Biol, 5, 15-22.  
19309264 K.A.Trumbull, and J.S.Beckman (2009).
A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.
  Antioxid Redox Signal, 11, 1627-1639.  
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.  
19369197 L.Banci, I.Bertini, M.Boca, V.Calderone, F.Cantini, S.Girotto, and M.Vieru (2009).
Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.
  Proc Natl Acad Sci U S A, 106, 6980-6985.
PDB codes: 3ecu 3ecv 3ecw
19271992 M.Chattopadhyay, and J.S.Valentine (2009).
Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS.
  Antioxid Redox Signal, 11, 1603-1614.  
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.  
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.