PDBsum entry 2vr7

Oxidoreductase

PDB id: 2vr7

Contents

Protein chain

154 a.a. *

Ligands

SO4 ×2

SCN ×4

Metals

_ZN ×6

_CU ×2

Waters ×624

* Residue conservation analysis

PDB id:

2vr7

Name:

Oxidoreductase

Title:

Crystal structure of g85r als mutant of human cu,zn superoxide dismutase (cuznsod) at 1.58 a resolution

Structure:

Superoxide dismutase [cu-zn]. Chain: a, f. Fragment: residues 2-154. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932

Resolution:

1.58Å R-factor: 0.137 R-free: 0.175

Authors:

S.Antonyuk,X.Cao,S.V.Seetharaman,L.J.Whitson,A.B.Taylor,S.P.Holloway, R.W.Strange,P.A.Doucette,A.Tiwari,L.J.Hayward,S.Padua,J.A.Cohlberg, J.Selverstone Valentine,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

Date:

28-Mar-08 Release date: 15-Apr-08

Protein chains

P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn] from Homo sapiens

Seq: 154 a.a.

Struc: 153 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.15.1.1 - superoxide dismutase.
• Reaction: 2 superoxide + 2 H⁺ = H2O2 + O2
• Cofactor: Fe cation or Mn(2+) or (Zn(2+) and Cu cation)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

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.

ABSTRACT

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.