AdipoRon: An anti-diabetes and anti-aging drug

抄録

Adiponectin (Ad) is an antidiabetic adipokine, which binds to its receptors AdipoR1/R2 (Nature, 2003), leading to activation of AMPK and PPAR pathways, respectively (Nature med. 2007, Nature 2010). Recently, small-molecule AdipoR agonist was shown to ameliorate diabetes and increase exercise endurance, and at the same time prolong shortened lifespan in obesity (Nature 2013). Although AdipoRs are predicted to contain seven-transmembrane (7TM) domains, with an internal N-terminus and an external C-terminus, which is opposite to GPCRs, crystal structures of AdipoRs remained to be determined.

In this study, we optimized properties of AdipoRs by mutations, and then used Fv fragment of an anti-AdipoR monoclonal antibody and lipidic cubic phase for crystallization. Then, we successfully determined crystal structures of human AdipoR1/R2, and found that overall structures of AdipoRs are indeed distinct from those of GPCRs (Nature 2015). Moreover, as for common functions of AdipoRs such as Ad binding, mutational analyses of conserved residues between AdipoR1/R2 shown by crystal structures revealed that Ad may broadly interact with extracellular surface of AdipoRs, in a different manner from previously anticipated. In contrast, as for specific functions of AdipoRs such as specific intracellular signal transduction pathways, mutational analyses of specific residues shown by crystal structures gave important insight into understanding each AdipoR specific intracellular signaling mechanisms.

The seven-transmembrane domain of both AdipoR1 and AdipoR2 was shown to have a cavity with a zinc-binding site, which contains unidentified extra electron densities. It was thus suggested that these electron densities may represent potential substrates for AdipoR hydrolytic activity or their products. For development of best-in-class AdipoR agonists, optimization of AdipoRon based on 3D structure of AdipoRon-AdipoR complex should be most important.

In conclusion, mutational analyses based on crystal structures revealed novel structural and functional properties of AdipoRs, including 7TM architecture and a putative Ad-binding surface, which are completely distinct from those of GPCRs, thus highlighting uniqueness of AdipoRs. This study should open new avenues toward elucidation of an unprecedented paradigm of signal transduction and development and optimization of AdipoR agonists.