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Crystal structures of the human adiponectin receptors.

Tanabe H., Fujii Y., Okada-Iwabu M., Iwabu M., Nakamura Y., Hosaka T., Motoyama K., Ikeda M., Wakiyama M., Terada T., Ohsawa N., Hato M., Ogasawara S., Hino T., Murata T., Iwata S., Hirata K., Kawano Y., Yamamoto M., Kimura-Someya T., Shirouzu M., Yamauchi T., Kadowaki T., Yokoyama S.

Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 Å resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.

Nature 520:312-316(2015) [PubMed] [Europe PMC]

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