Crystal structures of the human adiponectin receptors

摘要

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 A 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.%Adiponectin是一种抗糖尿病分子。在肥胖症和2-型糖尿病中,该分子的血浆水平降低。Adiponectin的补充据报道能够改善小鼠的葡萄糖耐受性和血脂异常。现在,Shigeyuki Yokoyama及同事分别以2.9 A和2.4 A的分辨率报告了人Adiponectin受体AdipoR1和AdipoR2的晶体结构。所获得的结构和功能信息也许可帮助用于治疗与肥胖相关疾病的Adiponectin受体激动剂的研发与优化。