Crystal structures of the human adiponectin receptors

  • Nature. 2015 Apr 16;520(7547):312-316. doi: 10.1038/nature14301.
Hiroaki Tanabe  1  2  3  4 ,  Yoshifumi Fujii  1  4 ,  Miki Okada-Iwabu  #  5  6 ,  Masato Iwabu  #  5  6  7 ,  Yoshihiro Nakamura  #  1  3  4 ,  Toshiaki Hosaka  1  3 ,  Kanna Motoyama  1 ,  Mariko Ikeda  1  3 ,  Motoaki Wakiyama  1  3 ,  Takaho Terada  1  4 ,  Noboru Ohsawa  1  3 ,  Masakatsu Hato  1  3 ,  Satoshi Ogasawara  8 ,  Tomoya Hino  8  9 ,  Takeshi Murata  1  8  9  10 ,  So Iwata  1  8  9  11  12  13 ,  Kunio Hirata  13 ,  Yoshiaki Kawano  13 ,  Masaki Yamamoto  13 ,  Tomomi Kimura-Someya  1  3 ,  Mikako Shirouzu  1  3 ,  Toshimasa Yamauchi  5  6  14 ,  Takashi Kadowaki  5  6 ,  Shigeyuki Yokoyama  1  2  4
Affiliations
  • 1. RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 2. Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 3. Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 4. RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
  • 5. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 6. Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 7. PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
  • 8. Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  • 9. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
  • 10. Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage, Chiba 263-8522, Japan.
  • 11. Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, UK.
  • 12. Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, UK.
  • 13. RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan.
  • 14. CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
  • # Contributed equally.
PMID: 25855295 DOI: 10.1038/nature14301
Abstract

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.