The finding by HUJI researchers uncovers a novel structure of an outer mitochondrial membrane [Fe-S] protein (mitoNEET) determined by X-ray crystallography (Fig 1)
MitoNEET is an outer mitochondrial membrane protein that binds pioglitzaone (ActosTM), an insulin-sensitizing drug of the thiazolidinedione class used in the treatment of Type II diabetes. This protein has a unique dimeric structure where the two components interact to form a new fold not previously seen in any Fe-S protein structures or in any know protein. This new fold forms a binding domain between two acid labile 2Fe-2S clusters.
Stabilized 2FE-2S cluster of mitoNEET is applicable for treating metabolic dysfunctional disorders, such as Type II diabetes.
This unique dimeric structure does not bare any resemblance to any previously reported Fe-S protein structure.
In this novel fold, the two protomers intertwine to form a unique two-domain structure: a beta cap domain and a cluster binding domain that cradles two labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing drug used in the treatment of Type 2 diabetes, stabilizes the protein against 2Fe-2S release.
Fig. 1: A cluster binding domain of mitoNEET containing 3 cysteine residues and 1 histidine residue, coordinating an acid-labile 2Fe-2S cluster
The new approach may have a significant impact at treating metabolic dysfunctional disorders, such as Type II Diabetes
The findings are not only related to diabetes but may have a much broader claim on the involvement of Fe-S in diseases in general.
Biol. Chem. 2007 Aug. 17 282(33)::23745-9. The outer mitochondrial membrane protein mitoNEET contains a novel redox-active 2FE-2S cluster. Wiley SE, Paddock ML, Abresch EC, Gross L, van der Geer P, Nechushtai R, Murphy AN, Jennings PA, Dixon JE.
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14342-7. MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA
Granted US 8,350,007