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

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

doi:10.1038/s41589-018-0131-3

Cited by 90 publications

(106 citation statements)

References 56 publications

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“…7b-f). In contrast to the peptide hormone GPCRs, several GPCRs with lipid ligands have gaps between TM1 and TM7 (S1P 1 , EP 4 , and TP) [26][27][28] , TM3 and TM4 (GPR40) 29 , and TM4 and TM5 (PAFR and LPA 6 ) 30,31 ( Supplementary Fig. 7g-l).…”

Section: Compound 21 Ecl2mentioning

confidence: 99%

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

et al. 2020

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Ghrelin is a gastric peptide hormone with important physiological functions. The unique feature of ghrelin is its Serine 3 acyl-modification, which is essential for ghrelin's activity. However, it remains to be elucidated why the acyl-modification of ghrelin is necessary for activity. To address these questions, we solved the crystal structure of the ghrelin receptor bound to antagonist. The ligand-binding pocket of the ghrelin receptor is bifurcated by a salt bridge between E124 and R283. A striking feature of the ligand-binding pocket of the ghrelin receptor is a wide gap (crevasse) between the TM6 and TM7 bundles that is rich in hydrophobic amino acids, including a cluster of phenylalanine residues. Mutagenesis analyses suggest that the interaction between the gap structure and the acyl acid moiety of ghrelin may participate in transforming the ghrelin receptor into an active conformation.

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Section: Compound 21 Ecl2mentioning

confidence: 99%

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

et al. 2020

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“…Other mutations in the pocket show promise, e.g., introducing Arg in 3.39 position was theoretically predicted as stabilizing mutation (Yasuda et al, 2017) expected to block the Na 1 pocket. This mutation recently helped to solve new structures of muscarinic acetylcholine receptor 2 (M2R) (Suno et al, 2018b) and EP4 prostaglandin receptor (Toyoda et al, 2019) in the inactive state.…”

Section: Structures Of Active State G-protein-coupled Receptors Are Imentioning

confidence: 99%

Harnessing Ion-Binding Sites for GPCR Pharmacology

et al. 2019

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“…Even within the α‐branch of class A, lysophosphatidic acid, sphingosine‐1‐phosphate, and cannabinoid receptors , which lack the canonical class A disulfide bridge between TM3 and ECL2, close off their binding sites mostly using their N terminus with minor ECL2 contributions. In contrast, prostaglandin receptors and rhodopsin display a tight lid formed from ECL2 with a β‐hairpin constrained to TM3 by the canonical class A disulfide bridge. The ECL2 backbone and disulfide location of MT receptors overlap remarkably well with that of solved prostaglandin and rhodopsin structures (Fig.…”

Section: Structures Of Human Mt Receptors and Their Implications For mentioning

confidence: 99%

Structural insights into melatonin receptors

2019

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The long-anticipated high-resolution structures of the human melatonin G protein-coupled receptors MT 1 and MT 2 , involved in establishing and maintaining circadian rhythm, were obtained in complex with two melatonin analogs and two approved anti-insomnia and antidepression drugs using X-ray free-electron laser serial femtosecond crystallography. The structures shed light on the overall conformation and unusual structural features of melatonin receptors, as well as their ligand binding sites and the melatonergic pharmacophore, thereby providing insights into receptor subtype selectivity. The structures revealed an occluded orthosteric ligand binding site with a membrane-buried channel for ligand entry in both receptors, and an additional putative ligand entry path in MT 2 from the extracellular side. This unexpected ligand entry mode contributes to facilitating the high specificity with which melatonin receptors bind their cognate ligand and exclude structurally similar molecules such as serotonin, the biosynthetic precursor of melatonin. Finally, the MT 2 structure allowed accurate mapping of type 2 diabetes-related single-nucleotide polymorphisms, where a clustering of residues in helices I and II on the protein-membrane interface was observed which could potentially influence receptor oligomerization. The role of receptor oligomerization is further discussed in light of the differential interaction of MT 1 and MT 2 with GPR50, a regulatory melatonin coreceptor. The melatonin receptor structures will facilitate design of selective tool compounds to further dissect the specific physiological function of each receptor subtype as well as provide a structural basis for next-generation sleeping aids and other drugs targeting these receptors with higher specificity and fewer side effects.

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

Cited by 90 publications

References 56 publications

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Harnessing Ion-Binding Sites for GPCR Pharmacology

Structural insights into melatonin receptors

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