5YHL

Crystal structure of the human prostaglandin E receptor EP4 in complex with Fab and an antagonist Br-derivative

Summary for 5YHL

• Entry DOI: 10.2210/pdb5yhl/pdb
• Related: 5WV2 5YFI
• Descriptor: Prostaglandin E2 receptor EP4 subtype, Heavy chain of Fab fragment, Light chain of Fab fragment, ... (4 entities in total)
• Functional Keywords: g-protein coupled receptor, lipid mediator, functional antibody, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 91717.84

Authors

Toyoda, Y.,Morimoto, K.,Suno, R.,Horita, S.,Iwata, S.,Kobayashi, T. (deposition date: 2017-09-28, release date: 2018-12-05, Last modification date: 2024-11-06)

Primary citation

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.
Ligand binding to human prostaglandin E receptor EP4at the lipid-bilayer interface.
Nat. Chem. Biol., 15:18-26, 2019

PubMed 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 PGE 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.

PubMed: 30510193
DOI: 10.1038/s41589-018-0131-3

Experimental method

X-RAY DIFFRACTION (4.2 Å)