TY - JOUR
T1 - Crystal structures of the human adiponectin receptors
AU - Tanabe, Hiroaki
AU - Fujii, Yoshifumi
AU - Okada-Iwabu, Miki
AU - Iwabu, Masato
AU - Nakamura, Yoshihiro
AU - Hosaka, Toshiaki
AU - Motoyama, Kanna
AU - Ikeda, Mariko
AU - Wakiyama, Motoaki
AU - Terada, Takaho
AU - Ohsawa, Noboru
AU - Hato, Masakatsu
AU - Ogasawara, Satoshi
AU - Hino, Tomoya
AU - Murata, Takeshi
AU - Iwata, So
AU - Hirata, Kunio
AU - Kawano, Yoshiaki
AU - Yamamoto, Masaki
AU - Kimura-Someya, Tomomi
AU - Shirouzu, Mikako
AU - Yamauchi, Toshimasa
AU - Kadowaki, Takashi
AU - Yokoyama, Shigeyuki
N1 - Funding Information:
Acknowledgements We are grateful to the staffs of BL32XU at SPring-8 (proposals 2012A1332, 2012B1453, 2013A1008, 2013A1008, 2013B1034, 2013B1007, 2014A1007, 2014A1008 and 2014A1186), beamline I24 at Diamond Light Source, and beamline X06SA at the Swiss Light Source for their assistance in data collection. We thank R. Akasaka for protein analysis, M. Toyama, M. Inoue, M. Goto, M. Aoki and K. Ishii for expression plasmid preparation, M. Nishimoto, Y. Tomabechi and Y. Terazawa for technical assistance with protein expression and purification, and Y. Nishibaba, M. Yuasa and A. Hayashi for technical assistance and support with the activity assays of the mutants. This work was supported by grants from the Targeted Proteins Research Program (S.Y., T.K., S.I. and M.Y.), the Platform for Drug Discovery, Informatics and Structural Life Science (S.Y. and M.Y.), a Grant-in-Aid for Specially Promoted Research (26000012) (T.K.), Grants-in-Aid for Scientific Research (S) (20229008, 25221307) (T.K.), a Grant-in-Aid for Scientific Research (B) (26293216) (M.O.-I.), a Grant-in-Aid for Young Scientists (A) (30557236) (M. Iwabu), and the Translational Research Network Program (M.O.-I.), from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the research acceleration program of the Japan Science and Technology Agency (S.I.), and by the BBSRC (BB/G02325/1) (S.I.). The authors are grateful for the use of the Membrane Protein Laboratoryfundedbythe Wellcome Trust(grant062164/Z/00/Z)(S.I.)atthe Diamond Light Source Limited.
Publisher Copyright:
©2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/4/15
Y1 - 2015/4/15
N2 - 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.
AB - 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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U2 - 10.1038/nature14301
DO - 10.1038/nature14301
M3 - Article
C2 - 25855295
AN - SCOPUS:84928409629
VL - 520
SP - 312
EP - 316
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7547
ER -