Structural Comparison Of A Diabetes Drug Target, Mitoneet, A 2Fe-2S Cluster Protein To Its More Stable Mutant, H87C

Abstract

MitoNEET, a recently discovered 2Fe-2S containing outer mitochondrial protein (1), was identified as a binding target for pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class used in the treatment of type 2 diabetes (2). MitoNEET possesses a unique dimeric structure, with a new fold (3). The pH sensitive lability of the 2Fe-2S cluster was attributed to protonation of the conserved solvent accessible His87 (Figure). Its replacement with Cys increased the stability of the cluster ∼10-fold (1). The crystal structure of the H87C mutant (1.8Å, Rfactor = 18%) shows that the Sγ of Cys87 remains at a similar position to the Nδ of His87 in the native (Figure). The only other change was a reorientation of Lys55. Thus, the increased stability of the HC87 mutant is attributed to the specific change in the ligation of the 2Fe-2S cluster, not a more global conformational change. (1) Wiley et al. (2007) J Biol Chem. 282, 23745-23749. (2) Colca et al. (2004) Am J Physiol Endocrinol Metab 286, E252-E260. (3) Paddock et al. (2007) Proc Natl. Acad. Sci USA 104, 14342-14347. ∗Supported by NIH (GM41637, GM54038 and DK5441).