PDBsum entry 1uxl

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
Protein chain
(+ 4 more) 153 a.a. *
SO4 ×8
_ZN ×10
_CU ×10
Waters ×2447
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: I113t mutant of human sod1
Structure: Superoxide dismutase [cu-zn]. Chain: a, b, c, d, e, f, g, h, i, j. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Expression_system_variant: yep351
Biol. unit: Dimer (from PDB file)
1.60Å     R-factor:   0.172     R-free:   0.196
Authors: M.A.Hough,J.G.Grossmann,S.V.Antonyuk,R.W.Strange,P.A.Doucett J.A.Rodriguez,L.J.Whitson,P.J.Hart,L.J.Hayward,J.S.Valentin S.S.Hasnain
Key ref:
M.A.Hough et al. (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. PubMed id: 15056757 DOI: 10.1073/pnas.0305143101
25-Feb-04     Release date:   19-Mar-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn]
154 a.a.
153 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: 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: 10.1073/pnas.0305143101 Proc Natl Acad Sci U S A 101:5976-5981 (2004)
PubMed id: 15056757  
Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants.
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, S.S.Hasnain.
More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile113Thr (I113T) mutants to 1.9 and 1.6 A, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80 degrees C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.
  Selected figure(s)  
Figure 1.
Fig. 1. Images of 2F[obs] - F[calc] electron density maps, contoured at 1.5 are shown for wtSOD (a): the Ala-4 side-chain C forms a 3.6-Å hydrophobic contact to the C 2 atom of Ile-113. (b) A4V: The mutation is clearly defined in the electron density. Hydrophobic close contacts are indicated by dashed lines. Steric constraints due to the bulkier Val side chain in the mutant structure cause a shift in the position of Ile-113 due to the replacement of the single 3.6-Å Ala-4C -Ile-113C 2 hydrophobic interaction with two others, namely from Val-4C 1 to Ile-113C 1 (3.8 Å) and Ile-113C 2 (3.9 Å). In addition, a contact is formed between Val-4C 2 and Ile-149C 2 (3.5 Å). (c) I113T: The close contact between Ala-4C and Ile-113C 2 is lost.
Figure 4.
Fig. 4. Two perpendicular views of the shapes reconstructed from the wild-type, A4V, and I113T scattering profiles shown in Fig. 3a. Each shape reconstruction is performed with a dimer obeying twofold symmetry in which each subunit is represented by closely packed spheres. The wild-type crystal structure (PDB ID code 1HL5 [PDB] ) has been superimposed in the scattering envelope of wtSOD1.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21104697 A.D.Schuyler, H.A.Carlson, and E.L.Feldman (2011).
Computational methods for identifying a layered allosteric regulatory mechanism for ALS-causing mutations of Cu-Zn superoxide dismutase 1.
  Proteins, 79, 417-427.  
20184893 C.Kayatekin, J.A.Zitzewitz, and C.R.Matthews (2010).
Disulfide-reduced ALS variants of Cu, Zn superoxide dismutase exhibit increased populations of unfolded species.
  J Mol Biol, 398, 320-331.  
20399791 C.Münch, and A.Bertolotti (2010).
Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants.
  J Mol Biol, 399, 512-525.  
20516618 I.Ascone, C.Savino, R.Kahn, and R.Fourme (2010).
Flexibility of the Cu,Zn superoxide dismutase structure investigated at 0.57 GPa.
  Acta Crystallogr D Biol Crystallogr, 66, 654-663.
PDB code: 3hw7
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
19563893 A.K.Holley, K.K.Kiningham, D.R.Spitz, D.P.Edwards, J.T.Jenkins, and M.R.Moore (2009).
Progestin stimulation of manganese superoxide dismutase and invasive properties in T47D human breast cancer cells.
  J Steroid Biochem Mol Biol, 117, 23-30.  
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.  
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.  
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.  
19439221 S.C.Barber, A.Higginbottom, R.J.Mead, S.Barber, and P.J.Shaw (2009).
An in vitro screening cascade to identify neuroprotective antioxidants in ALS.
  Free Radic Biol Med, 46, 1127-1138.  
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.  
19751676 T.Schmidlin, B.K.Kennedy, and V.Daggett (2009).
Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.
  Biophys J, 97, 1709-1718.  
19696882 V.Castillo, and S.Ventura (2009).
Amyloidogenic regions and interaction surfaces overlap in globular proteins related to conformational diseases.
  PLoS Comput Biol, 5, e1000476.  
19325915 Z.A.Oztug Durer, J.A.Cohlberg, P.Dinh, S.Padua, K.Ehrenclou, S.Downes, J.K.Tan, Y.Nakano, C.J.Bowman, J.L.Hoskins, C.Kwon, A.Z.Mason, J.A.Rodriguez, P.A.Doucette, B.F.Shaw, and J.Selverstone Valentine (2009).
Loss of metal ions, disulfide reduction and mutations related to familial ALS promote formation of amyloid-like aggregates from superoxide dismutase.
  PLoS ONE, 4, e5004.  
19436494 A.Nordlund, and M.Oliveberg (2008).
SOD1-associated ALS: a promising system for elucidating the origin of protein-misfolding disease.
  HFSP J, 2, 354-364.  
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.  
19052230 F.Ding, and N.V.Dokholyan (2008).
Dynamical roles of metal ions and the disulfide bond in Cu, Zn superoxide dismutase folding and aggregation.
  Proc Natl Acad Sci U S A, 105, 19696-19701.  
18156683 H.B.Stuhrmann (2008).
Small-angle scattering and its interplay with crystallography, contrast variation in SAXS and SANS.
  Acta Crystallogr A, 64, 181-191.  
18666828 Q.Wang, J.L.Johnson, N.Y.Agar, and J.N.Agar (2008).
Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival.
  PLoS Biol, 6, e170.  
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
16945901 A.Ferri, M.Cozzolino, C.Crosio, M.Nencini, A.Casciati, E.B.Gralla, G.Rotilio, J.S.Valentine, and M.T.Carrì (2006).
Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials.
  Proc Natl Acad Sci U S A, 103, 13860-13865.  
16798882 A.Nordlund, and M.Oliveberg (2006).
Folding of Cu/Zn superoxide dismutase suggests structural hotspots for gain of neurotoxic function in ALS: parallels to precursors in amyloid disease.
  Proc Natl Acad Sci U S A, 103, 10218-10223.  
17020617 I.W.Boucher, A.M.Brzozowski, J.A.Brannigan, C.Schnick, D.J.Smith, S.A.Kyes, and A.J.Wilkinson (2006).
The crystal structure of superoxide dismutase from Plasmodium falciparum.
  BMC Struct Biol, 6, 20.
PDB code: 2bpi
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.  
16636274 Y.Furukawa, R.Fu, H.X.Deng, T.Siddique, and T.V.O'Halloran (2006).
Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.
  Proc Natl Acad Sci U S A, 103, 7148-7153.  
16771675 Y.Furukawa, and T.V.O'Halloran (2006).
Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis.
  Antioxid Redox Signal, 8, 847-867.  
16287844 C.D.Carter, L.E.Kitchen, W.C.Au, C.M.Babic, and M.A.Basrai (2005).
Loss of SOD1 and LYS7 sensitizes Saccharomyces cerevisiae to hydroxyurea and DNA damage agents and downregulates MEC1 pathway effectors.
  Mol Cell Biol, 25, 10273-10285.  
16169146 F.Hoerndli, D.C.David, and J.Götz (2005).
Functional Genomics meets neurodegenerative disorders. Part II: application and data integration.
  Prog Neurobiol, 76, 169-188.  
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.  
15987780 M.J.Lindberg, R.Byström, N.Boknäs, P.M.Andersen, and M.Oliveberg (2005).
Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants.
  Proc Natl Acad Sci U S A, 102, 9754-9759.  
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.  
15738401 S.S.Ray, R.J.Nowak, R.H.Brown, and P.T.Lansbury (2005).
Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation.
  Proc Natl Acad Sci U S A, 102, 3639-3644.  
15272266 E.Bossy-Wetzel, R.Schwarzenbacher, and S.A.Lipton (2004).
Molecular pathways to neurodegeneration.
  Nat Med, 10, S2-S9.  
15522970 M.J.Lindberg, J.Normark, A.Holmgren, and M.Oliveberg (2004).
Folding of human superoxide dismutase: disulfide reduction prevents dimerization and produces marginally stable monomers.
  Proc Natl Acad Sci U S A, 101, 15893-15898.  
15079068 S.S.Ray, and P.T.Lansbury (2004).
A possible therapeutic target for Lou Gehrig's disease.
  Proc Natl Acad Sci U S A, 101, 5701-5702.  
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.