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.

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