2HT9

The structure of dimeric human glutaredoxin 2

Summary for 2HT9

• Entry DOI: 10.2210/pdb2ht9/pdb
• Descriptor: Glutaredoxin-2, 12-mer peptide, GLUTATHIONE, ... (5 entities in total)
• Functional Keywords: thioredoxin fold, iron-sulfur cluster, 2fe2s, structural genomics, structural genomics consortium, sgc, oxidoreductase
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Mitochondrion. Isoform 2: Nucleus: Q9NS18
• Total number of polymer chains: 3
• Total formula weight: 35631.97

Authors

Johansson, C.,Smee, C.,Kavanagh, K.L.,Debreczeni, J.,von Delft, F.,Gileadi, O.,Arrowsmith, C.,Weigelt, J.,Edwards, A.,Sundstrom, M.,Oppermann, U.,Structural Genomics Consortium (SGC) (deposition date: 2006-07-25, release date: 2006-08-29, Last modification date: 2023-10-25)

Primary citation

Johansson, C.,Kavanagh, K.L.,Gileadi, O.,Oppermann, U.
Reversible sequestration of active site cysteines in a 2Fe-2S-bridged dimer provides a mechanism for glutaredoxin 2 regulation in human mitochondria
J.Biol.Chem., 282:3077-3082, 2007

PubMed Abstract: Human mitochondrial glutaredoxin 2 (GLRX2), which controls intracellular redox balance and apoptosis, exists in a dynamic equilibrium of enzymatically active monomers and quiescent dimers. Crystal structures of both monomeric and dimeric forms of human GLRX2 reveal a distinct glutathione binding mode and show a 2Fe-2S-bridged dimer. The iron-sulfur cluster is coordinated through the N-terminal active site cysteine, Cys-37, and reduced glutathione. The structures indicate that the enzyme can be inhibited by a high GSH/GSSG ratio either by forming a 2Fe-2S-bridged dimer that locks away the N-terminal active site cysteine or by binding non-covalently and blocking the active site as seen in the monomer. The properties that permit GLRX2, and not other glutaredoxins, to form an iron-sulfur-containing dimer are likely due to the proline-to-serine substitution in the active site motif, allowing the main chain more flexibility in this area and providing polar interaction with the stabilizing glutathione. This appears to be a novel use of an iron-sulfur cluster in which binding of the cluster inactivates the protein by sequestering active site residues and where loss of the cluster through changes in subcellular redox status creates a catalytically active protein. Under oxidizing conditions, the dimers would readily separate into iron-free active monomers, providing a structural explanation for glutaredoxin activation under oxidative stress.

PubMed: 17121859
DOI: 10.1074/jbc.M608179200

Experimental method

X-RAY DIFFRACTION (1.9 Å)