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2nnx

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[[Image:2nnx.gif|left|200px]]
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{{STRUCTURE_2nnx| PDB=2nnx | SCENE= }}
{{STRUCTURE_2nnx| PDB=2nnx | SCENE= }}
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'''Crystal Structure of the H46R, H48Q double mutant of human [Cu-Zn] Superoxide Dismutase'''
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===Crystal Structure of the H46R, H48Q double mutant of human [Cu-Zn] Superoxide Dismutase===
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==Overview==
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A subset of superoxide dismutase 1 (Cu/Zn-SOD1) mutants that cause familial amyotrophic lateral sclerosis (FALS) have heightened reactivity with (-)ONOO and H(2)O(2) in vitro. This reactivity requires a copper ion bound in the active site and is a suggested mechanism of motor neuron injury. However, we have found that transgenic mice that express SOD1-H46R/H48Q, which combines natural FALS mutations at ligands for copper and which is inactive, develop motor neuron disease. Using a direct radioactive copper incorporation assay in transfected cells and the established tools of single crystal x-ray diffraction, we now demonstrate that this variant does not stably bind copper. We find that single mutations at copper ligands, including H46R, H48Q, and a quadruple mutant H46R/H48Q/H63G/H120G, also diminish the binding of radioactive copper. Further, using native polyacrylamide gel electrophoresis and a yeast two-hybrid assay, the binding of copper was found to be related to the formation of the stable dimeric enzyme. Collectively, our data demonstrate a relationship between copper and assembly of SOD1 into stable dimers and also define disease-causing SOD1 mutants that are unlikely to robustly produce toxic radicals via copper-mediated chemistry.
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{{ABSTRACT_PUBMED_17092942}}
==Disease==
==Disease==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Superoxide acceptor]]
[[Category: Superoxide acceptor]]
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Revision as of 12:33, 27 July 2008

Image:2nnx.png

Template:STRUCTURE 2nnx

Contents

Crystal Structure of the H46R, H48Q double mutant of human [Cu-Zn] Superoxide Dismutase

Template:ABSTRACT PUBMED 17092942

Disease

Known disease associated with this structure: Amyotrophic lateral sclerosis, due to SOD1 deficiency OMIM:[147450]

About this Structure

2NNX is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Disease-associated mutations at copper ligand histidine residues of superoxide dismutase 1 diminish the binding of copper and compromise dimer stability., Wang J, Caruano-Yzermans A, Rodriguez A, Scheurmann JP, Slunt HH, Cao X, Gitlin J, Hart PJ, Borchelt DR, J Biol Chem. 2007 Jan 5;282(1):345-52. Epub 2006 Nov 8. PMID:17092942

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