PDBsum entry 1var

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protein metals Protein-protein interface(s) links
Oxidoreductase PDB id
Protein chains
198 a.a. *
MN3 ×2
Waters ×523
* Residue conservation analysis
PDB id:
Name: Oxidoreductase
Title: Mitochondrial manganese superoxide dismutase variant with ile 58 replaced by thr
Structure: Manganese superoxide dismutase. Chain: a, b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: kidney. Gene: human kidney sod2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PDB file)
2.50Å     R-factor:   0.170    
Authors: G.E.O.Borgstahl,H.E.Parge,J.A.Tainer
Key ref:
G.E.Borgstahl et al. (1996). Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface. Biochemistry, 35, 4287-4297. PubMed id: 8605177 DOI: 10.1021/bi951892w
04-Jan-96     Release date:   10-Jun-96    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P04179  (SODM_HUMAN) -  Superoxide dismutase [Mn], mitochondrial
222 a.a.
198 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: Iron or manganese or (zinc and copper)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     superoxide dismutase activity     2 terms  


    Added reference    
DOI no: 10.1021/bi951892w Biochemistry 35:4287-4297 (1996)
PubMed id: 8605177  
Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface.
G.E.Borgstahl, H.E.Parge, M.J.Hickey, M.J.Johnson, M.Boissinot, R.A.Hallewell, J.R.Lepock, D.E.Cabelli, J.A.Tainer.
Human manganese superoxide dismutase (MnSOD) is a homotetrameric enzyme which protects mitochondria against oxygen-mediated free radical damage. Within each subunit, both the N-terminal helical hairpin and C-terminal alpha/beta domains contribute ligands to the catalytic manganese site. Two identical four-helix bundles, symmetrically assembled from the N-terminal helical hairpins, form a novel tetrameric interface that stabilizes the active sites. The 2.5 A crystallographic structure of the naturally occurring polymorphic variant Ile58Thr MnSOD reveals that the helical hairpin mutation Thr58 causes two packing defects in each of the two four-helix bundles of the tetrameric interface. Similar mutations, expected to cause packing defects in the Cu,ZnSOD dimer interface, are associated with the degenerative disease amyotrophic lateral sclerosis. Ile58Thr MnSOD is primarily dimeric in solution and is significantly less thermostable than the normal enzyme, with decreases of 15 degrees C in the main melting temperature and 20 degrees C in the heat-inactivation temperature. Consequently, this mutant MnSOD is compromised at normal body temperatures: thermal inactivation, predicted from the decrease in thermal stability, occurs with a theoretical half-life of only 3.2 h at 37 degrees C (1.4 h at 41 degrees C), compared with 3.1 years for native MnSOD. This prediction is supported by direct measurements: incubation at 41.7 degrees C for 3 h has no effect on the activity of native MnSOD but completely inactivates mutant MnSOD. Rapid inactivation of Ile58Thr MnSOD at the elevated temperatures associated with fever and inflammation could provide an early advantage by killing infected cells, but also would increase superoxide-mediated oxidative damage and perhaps contribute to late-onset diseases.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20471444 M.Maes, P.Galecki, Y.S.Chang, and M.Berk (2011).
A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.
  Prog Neuropsychopharmacol Biol Psychiatry, 35, 676-692.  
19405048 D.Hernandez-Saavedra, and J.M.McCord (2009).
Association of a new intronic polymorphism of the SOD2 gene (G1677T) with cancer.
  Cell Biochem Funct, 27, 223-227.  
19063897 D.S.Shin, M.Didonato, D.P.Barondeau, G.L.Hura, C.Hitomi, J.A.Berglund, E.D.Getzoff, S.C.Cary, and J.A.Tainer (2009).
Superoxide dismutase from the eukaryotic thermophile Alvinella pompejana: structures, stability, mechanism, and insights into amyotrophic lateral sclerosis.
  J Mol Biol, 385, 1534-1555.
PDB codes: 3f7k 3f7l
19384983 I.Castellano, F.Cecere, A.De Vendittis, R.Cotugno, A.Chambery, A.Di Maro, A.Michniewicz, G.Parlato, M.Masullo, E.V.Avvedimento, E.De Vendittis, and M.R.Ruocco (2009).
Rat mitochondrial manganese superoxide dismutase: Amino acid positions involved in covalent modifications, activity, and heat stability.
  Biopolymers, 91, 1215-1226.  
19265433 J.J.Perry, A.S.Hearn, D.E.Cabelli, H.S.Nick, J.A.Tainer, and D.N.Silverman (2009).
Contribution of human manganese superoxide dismutase tyrosine 34 to structure and catalysis.
  Biochemistry, 48, 3417-3424.
PDB codes: 1zsp 1zte 1zuq 2p4k
19477268 L.Miao, and D.K.St Clair (2009).
Regulation of superoxide dismutase genes: implications in disease.
  Free Radic Biol Med, 47, 344-356.  
19788422 M.Grey, S.Yainoy, V.Prachayasittikul, and L.Bülow (2009).
A superoxide dismutase-human hemoglobin fusion protein showing enhanced antioxidative properties.
  FEBS J, 276, 6195-6203.  
18466086 R.C.Martin, D.F.Barker, M.A.Doll, S.R.Pine, L.Mechanic, E.D.Bowman, C.C.Harris, and D.W.Hein (2008).
Manganese superoxide dismutase gene coding region polymorphisms lack clinical incidence in general population.
  DNA Cell Biol, 27, 321-323.  
17912757 R.Wintjens, D.Gilis, and M.Rooman (2008).
Mn/Fe superoxide dismutase interaction fingerprints and prediction of oligomerization and metal cofactor from sequence.
  Proteins, 70, 1564-1577.  
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
18078545 C.D.Putnam, M.Hammel, G.L.Hura, and J.A.Tainer (2007).
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution.
  Q Rev Biophys, 40, 191-285.  
16550599 A.Mancini, A.Borrelli, A.Schiattarella, S.Fasano, A.Occhiello, A.Pica, P.Sehr, M.Tommasino, J.P.Nüesch, and J.Rommelaere (2006).
Tumor suppressive activity of a variant isoform of manganese superoxide dismutase released by a human liposarcoma cell line.
  Int J Cancer, 119, 932-943.  
16630148 J.C.Mak, H.C.Leung, S.P.Ho, F.W.Ko, A.H.Cheung, M.S.Ip, and M.M.Chan-Yeung (2006).
Polymorphisms in manganese superoxide dismutase and catalase genes: functional study in Hong Kong Chinese asthma patients.
  Clin Exp Allergy, 36, 440-447.  
16910776 Y.Zhang, B.J.Smith, and L.W.Oberley (2006).
Enzymatic activity is necessary for the tumor-suppressive effects of MnSOD.
  Antioxid Redox Signal, 8, 1283-1293.  
14638684 A.S.Hearn, L.Fan, J.R.Lepock, J.P.Luba, W.B.Greenleaf, D.E.Cabelli, J.A.Tainer, H.S.Nick, and D.N.Silverman (2004).
Amino acid substitution at the dimeric interface of human manganese superoxide dismutase.
  J Biol Chem, 279, 5861-5866.
PDB codes: 1pl4 1pm9
15535847 Q.Cai, X.O.Shu, W.Wen, J.R.Cheng, Q.Dai, Y.T.Gao, and W.Zheng (2004).
Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study.
  Breast Cancer Res, 6, R647-R655.  
15622715 S.A.Nowell, J.Ahn, and C.B.Ambrosone (2004).
Gene-nutrient interactions in cancer etiology.
  Nutr Rev, 62, 427-438.  
14683419 S.C.Lymberis, P.K.Parhar, E.Katsoulakis, and S.C.Formenti (2004).
Pharmacogenomics and breast cancer.
  Pharmacogenomics, 5, 31-55.  
12618592 A.Sutton, H.Khoury, C.Prip-Buus, C.Cepanec, D.Pessayre, and F.Degoul (2003).
The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.
  Pharmacogenetics, 13, 145-157.  
12618590 D.St Clair, and E.Kasarskis (2003).
Genetic polymorphism of the human manganese superoxide dismutase: what difference does it make?
  Pharmacogenetics, 13, 129-130.  
12707956 E.Pegoraro, A.Vettori, M.L.Valentino, A.Molon, M.L.Mostacciuolo, N.Howell, and V.Carelli (2003).
X-inactivation pattern in multiple tissues from two Leber's hereditary optic neuropathy (LHON) patients.
  Am J Med Genet A, 119, 37-40.  
12888106 K.Mitrunen, and A.Hirvonen (2003).
Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism.
  Mutat Res, 544, 9.  
12683635 T.Kamatani, T.Yamamoto, K.Yoneda, and T.Osaki (2003).
Polymorphic mutations of the Mn-SOD gene in intact human lymphocytes and oral squamous cell carcinoma cell lines.
  Biochem Cell Biol, 81, 43-50.  
  11299047 D.A.Chistyakov, K.V.Savost'anov, E.V.Zotova, and V.V.Nosikov (2001).
Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus.
  BMC Med Genet, 2, 4.  
11491657 L.W.Oberley (2001).
Anticancer therapy by overexpression of superoxide dismutase.
  Antioxid Redox Signal, 3, 461-472.  
11679722 P.Taylor, M.Bilsland, and M.D.Walkinshaw (2001).
A new conformation of the integrin-binding fragment of human VCAM-1 crystallizes in a highly hydrated packing arrangement.
  Acta Crystallogr D Biol Crystallogr, 57, 1579-1583.
PDB code: 1ij9
11456495 W.Ranatunga, D.Jackson, R.A.Flowers II, and G.E.Borgstahl (2001).
Human RAD52 protein has extreme thermal stability.
  Biochemistry, 40, 8557-8562.  
10852710 V.J.Lévêque, M.E.Stroupe, J.R.Lepock, D.E.Cabelli, J.A.Tainer, H.S.Nick, and D.N.Silverman (2000).
Multiple replacements of glutamine 143 in human manganese superoxide dismutase: effects on structure, stability, and catalysis.
  Biochemistry, 39, 7131-7137.
PDB code: 1em1
10488113 C.A.Ramilo, V.Leveque, Y.Guan, J.R.Lepock, J.A.Tainer, H.S.Nick, and D.N.Silverman (1999).
Interrupting the hydrogen bond network at the active site of human manganese superoxide dismutase.
  J Biol Chem, 274, 27711-27716.
PDB code: 2gds
10490277 E.W.Lam, R.Zwacka, E.A.Seftor, D.R.Nieva, B.L.Davidson, J.F.Engelhardt, M.J.Hendrix, and L.W.Oberley (1999).
Effects of antioxidant enzyme overexpression on the invasive phenotype of hamster cheek pouch carcinoma cells.
  Free Radic Biol Med, 27, 572-579.  
9589371 M.Tomblyn, E.J.Kasarskis, Y.Xu, and D.K.St Clair (1998).
Distribution of MnSOD polymorphisms in sporadic ALS patients.
  J Mol Neurosci, 10, 65-66.  
9537987 Y.Guan, M.J.Hickey, G.E.Borgstahl, R.A.Hallewell, J.R.Lepock, D.O'Connor, Y.Hsieh, H.S.Nick, D.N.Silverman, and J.A.Tainer (1998).
Crystal structure of Y34F mutant human mitochondrial manganese superoxide dismutase and the functional role of tyrosine 34.
  Biochemistry, 37, 4722-4730.
PDB codes: 1ap5 1ap6
9537988 Y.Hsieh, Y.Guan, C.Tu, P.J.Bratt, A.Angerhofer, J.R.Lepock, M.J.Hickey, J.A.Tainer, H.S.Nick, and D.N.Silverman (1998).
Probing the active site of human manganese superoxide dismutase: the role of glutamine 143.
  Biochemistry, 37, 4731-4739.
PDB code: 1qnm
9095410 R.Liu, T.D.Oberley, and L.W.Oberley (1997).
Transfection and expression of MnSOD cDNA decreases tumor malignancy of human oral squamous carcinoma SCC-25 cells.
  Hum Gene Ther, 8, 585-595.  
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.