MitoNEET is a protein of unknown function present in the mitochondrial membrane that was recently shown to bind specifically the antidiabetic drug pioglizatone. Here, we report the crystal structure of the soluble domain (residues 32-108) of human mitoNEET at 1.8-Å resolution. The structure reveals an intertwined homodimer, and each subunit was observed to bind a [2Fe-2S] cluster. The [2Fe-2S] ligation pattern of three cysteines and one histidine differs from the known pattern of four cysteines in most cases or two cysteines and two histidines as observed in Rieske proteins. The [2Fe-2S] cluster is packed in a modular structure formed by 17 consecutive residues. The cluster-binding motif is conserved in at least seven distinct groups of proteins from bacteria, archaea, and eukaryotes, which show a consensus sequence of (hb)-C-X1-C-X2-(S/T)-X3-P-(hb)-C-D-X2-H, where hb represents a hydrophobic residue; we term this a CCCH-type [2Fe-2S] binding motif. The nine conserved residues in the motif contribute to iron ligation and structure stabilization. UV-visible absorption spectra indicated that mitoNEET can exist in oxidized and reduced states. Our study suggests an electron transfer function for mitoNEET and for other proteins containing the CCCH motif.2Fe-2S ͉ thiazolidinediones ͉ mitochondria T ype 2 diabetes is a growing global health problem characterized by insulin resistance and pancreatic -cell dysfunction (1). Thiazolidinediones (TZDs) are a class of insulinsensitizing drugs used for treatment of type 2 diabetes (2), which includes rosiglitazone and pioglitazone currently in clinic use. The mechanism of action of TZDs has been generally attributed to their direct activation of peroxisome proliferator-activated receptor-␥, a ligand-binding nuclear receptor important for adipocyte differentiation and glucose homeostasis (3). However, accumulating evidence suggests that TZDs may also exert effects via a peroxisome proliferator-activated receptor-␥-independent pathway, particularly through modulation of mitochondrial activity (4-6). Colca et al. (7) have recently identified a protein in the mitochondrial membrane that crosslinks with photo-affinitylabeled pioglitazone (7). The crosslink could be competed by unlabeled pioglitazone, suggesting specificity in TZD binding. The protein was named mitoNEET because of its mitochondrial location and because of the presence of the sequence motif Asn-Glu-Glu-Thr (''NEET''). MitoNEET has a putative Nterminal transmembrane helix, which likely serves as a membrane anchor, and several invariant cysteine and histidine residues, which suggests that mitoNEET contains a CDGSH-type zinc finger (Fig. 1). However, its sequence is not homologous to any protein or domain of known function. Elucidation of the function and structure of mitoNEET is important to reveal its biological activity, to understand the pharmacology of TZDs, and to aid in the design of more potent antidiabetic drugs. Here, we show by structural characterization that mitoNEET is a previously unrecognized iron-sulfu...
Recent advances in the synthesis of axially chiral biarylsviatransition metal-catalysed asymmetric C–H functionalization are reported.
The alkenylation reactions of 8-methylquinolines with alkynes, catalyzed by [{Cp*RhCl2}2], proceeds efficiently to give 8-allylquinolines in good yields by C(sp(3))-H bond activation. These reactions are highly regio- and stereoselective. A catalytically competent five-membered rhodacycle has been structurally characterized, thus revealing a key intermediate in the catalytic cycle.
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