FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcriptional factor implicated in regulating adipogenesis, glucose homeostasis, and in mediating the action of the insulin sensitizing anti-diabetic thiazolidinedione (TZD) compounds. [3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-H-benzimidazole-5-carboxamide] (FK614) is a structurally novel PPARgamma agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARgamma ligand with specific transactivation properties that are dependent upon the context of coactivators.

Mechanisms of drug/H+ antiport: complete cysteine-scanning mutagenesis and the protein engineering approach.

The notorious difficulty of elucidating structures of membrane transporters by crystallography has long prevented our understanding of active transport mechanism coupled with ion/proton transport. The determination of the first crystal structure of the drug/H+ antiporter AcrB was a breakthrough for structure-based understanding of drug/H+ antiport. However, although AcrB is a major multidrug exporter in Gram-negative organisms, the majority of bacterial drug exporters are major facilitator superfamily (MFS) drug transporters.