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Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface.

Toyoda Y, Morimoto K, Suno R, Horita S, Yamashita K, Hirata K, Sekiguchi Y, Yasuda S, Shiroishi M, Shimizu T, Urushibata Y, Kajiwara Y, Inazumi T, Hotta Y, Asada H, Nakane T, Shiimura Y, Nakagita T, Tsuge K, Yoshida S, Kuribara T, Hosoya T, Sugimoto Y, Nomura N, Sato M, Hirokawa T, Kinoshita M, Murata T, Takayama K, Yamamoto M, Narumiya S, Iwata S, Kobayashi T
Nat Chem Biol 15 18-26 (2019)
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Cited: 50 times
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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.

Reviews - 5yhl mentioned but not cited (5)

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Articles - 5yhl mentioned but not cited (2)

  1. Functional rewiring of G protein-coupled receptor signaling in human labor. Walker AR, Larsen CB, Kundu S, Stavrinidis C, Kim SH, Inoue A, Woodward DF, Lee YS, Migale R, MacIntyre DA, Terzidou V, Fanelli F, Khanjani S, Bennett PR, Hanyaloglu AC. Cell Rep 40 111318 (2022)
  2. Improved homology modeling of the human & rat EP4 prostanoid receptors. Holt MC, Ho CS, Morano MI, Barrett SD, Stein AJ. BMC Mol Cell Biol 20 37 (2019)


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