Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-01

AUTHORS

Yosuke Toyoda, Kazushi Morimoto, Ryoji Suno, Shoichiro Horita, Keitaro Yamashita, Kunio Hirata, Yusuke Sekiguchi, Satoshi Yasuda, Mitsunori Shiroishi, Tomoko Shimizu, Yuji Urushibata, Yuta Kajiwara, Tomoaki Inazumi, Yunhon Hotta, Hidetsugu Asada, Takanori Nakane, Yuki Shiimura, Tomoya Nakagita, Kyoshiro Tsuge, Suguru Yoshida, Tomoko Kuribara, Takamitsu Hosoya, Yukihiko Sugimoto, Norimichi Nomura, Miwa Sato, Takatsugu Hirokawa, Masahiro Kinoshita, Takeshi Murata, Kiyoshi Takayama, Masaki Yamamoto, Shuh Narumiya, So Iwata, Takuya Kobayashi

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. More... »

PAGES

18-26

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41589-018-0131-3

    DOI

    http://dx.doi.org/10.1038/s41589-018-0131-3

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1110288622

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30510193


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