1P1V

Crystal Structure of FALS-associated human Copper-Zinc Superoxide Dismutase (CuZnSOD) Mutant D125H to 1.4A

Summary for 1P1V

• Entry DOI: 10.2210/pdb1p1v/pdb
• Related: 1AZV 1OEZ 1OZT 1OZU
• Descriptor: Superoxide dismutase [Cu-Zn], SULFATE ION, ZINC ION, ... (4 entities in total)
• Functional Keywords: beta-barrel, bound anion at copper site, cuznsod peroxidation mechanism, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00441
• Total number of polymer chains: 3
• Total formula weight: 48280.51

Authors

Elam, J.S.,Malek, K.,Rodriguez, J.A.,Doucette, P.A.,Taylor, A.B.,Hayward, L.J.,Cabelli, D.E.,Valentine, J.S.,Hart, P.J. (deposition date: 2003-04-14, release date: 2003-08-26, Last modification date: 2021-10-27)

Primary citation

Elam, J.S.,Malek, K.,Rodriguez, J.A.,Doucette, P.A.,Taylor, A.B.,Hayward, L.J.,Cabelli, D.E.,Valentine, J.S.,Hart, P.J.
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, 2003

PubMed 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.

PubMed: 12649272
DOI: 10.1074/jbc.M300484200

Experimental method

X-RAY DIFFRACTION (1.4 Å)