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Nature. 2015 Apr 16;520(7547):312-316. doi: 10.1038/nature14301. Epub 2015 Apr 8.

Crystal structures of the human adiponectin receptors.

Tanabe H1,2,3,4, Fujii Y1,4, Okada-Iwabu M#5,6, Iwabu M#5,6,7, Nakamura Y#1,3,4, Hosaka T1,3, Motoyama K1, Ikeda M1,3, Wakiyama M1,3, Terada T1,4, Ohsawa N1,3, Hato M1,3, Ogasawara S8, Hino T8,9, Murata T1,8,9,10, Iwata S1,8,9,11,12,13, Hirata K13, Kawano Y13, Yamamoto M13, Kimura-Someya T1,3, Shirouzu M1,3, Yamauchi T5,6,14, Kadowaki T5,6, Yokoyama S1,2,4.

Author information

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

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.

PMID:
25855295
PMCID:
PMC4477036
DOI:
10.1038/nature14301
[Indexed for MEDLINE]
Free PMC Article

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