Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface
Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface
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DOI：
10.1038/s41589-018-0131-3
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发表时间：
2019-01-01
影响因子：
14.8
通讯作者：
Kobayashi, Takuya
中科院分区：
文献类型：
--
作者：
Toyoda, Yosuke;Morimoto, Kazushi;Kobayashi, Takuya
前列腺素E受体EP 4是一种G蛋白偶联受体，与癌症和自身免疫性疾病等疾病有关。在这里，我们报告的晶体结构的人EP 4在其拮抗剂ONO-AE 3 -208和抑制性抗体在3.2埃分辨率的复合物。该结构揭示了细胞外表面被细胞外环封闭，并且拮抗剂位于与脂质双层的界面处，靠近第七跨膜结构域中高度保守的Arg 316残基。功能和对接研究表明，天然激动剂PGE（2）以类似的方式结合。该结构信息还提供了从膜双层到EP 4结合口袋的配体进入途径的洞察。此外，结构揭示了抗体变构影响EP 4的配体结合。这些结果将有助于设计新的治疗药物，靶向这一受体家族的正构和变构位点。
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 angstrom 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 trans-membrane domain. Functional and docking studies demonstrate that the natural agonist PGE(2) 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.