| Literature DB >> 30510193 |
Yosuke Toyoda1,2, Kazushi Morimoto1, Ryoji Suno1, Shoichiro Horita1, Keitaro Yamashita3, Kunio Hirata3, Yusuke Sekiguchi1, Satoshi Yasuda4,5, Mitsunori Shiroishi6,7, Tomoko Shimizu8, Yuji Urushibata8, Yuta Kajiwara9,10, Tomoaki Inazumi11, Yunhon Hotta1, Hidetsugu Asada1,12, Takanori Nakane1, Yuki Shiimura1,12, Tomoya Nakagita1, Kyoshiro Tsuge11, Suguru Yoshida13, Tomoko Kuribara13, Takamitsu Hosoya7,13, Yukihiko Sugimoto11,14, Norimichi Nomura1,12, Miwa Sato15, Takatsugu Hirokawa7,10,16, Masahiro Kinoshita5, Takeshi Murata4,7, Kiyoshi Takayama8, Masaki Yamamoto3,7, Shuh Narumiya17,18, So Iwata19,20,21, Takuya Kobayashi22,23,24,25.
Abstract
Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.Entities:
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Year: 2018 PMID： 30510193 DOI： 10.1038/s41589-018-0131-3
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040