Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex

Suno, Ryoji; Sugita, Yukihiko; Morimoto, Kazushi; Takazaki, Hiroko; Tsujimoto, Hirokazu; Hirose, Mika; Suno-Ikeda, Chiyo; Nomura, Norimichi; Hino, Tsuneo; Inoue, Asuka; Iwasaki, Katsunori; Kato, Takayuki; Iwata, So; Kobayashi, Takuya

doi:10.1016/j.celrep.2022.111323

Cited by 13 publications

(10 citation statements)

References 37 publications

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“…Finally, we tested whether alterations in the ICL2 sequence would affect ETB-Gs coupling. As described above, the bulky hydrophobic residue 34.51 of ICL2 makes an extensive contact with the hydrophobic pocket of Gαs (Figure S2A), and mutations of the residue 34.51 into another smaller residues reduce GPCR-Gs coupling or switched GPCR-Gs coupling to GPCR-Gi coupling 24,[33][34][35] . Furthermore, introducing large hydrophobic amino acids into the residue 34.51 switched GPCR-Gi coupling to GPCR-Gs coupling 36 .…”

Section: Role Of Icl2 In Etb-gi1 or Etb-gq Couplingmentioning

confidence: 81%

Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq

Ham,

Shihoya,

Nureki

et al. 2024

Preprint

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The endothelin receptor type B (ETB) exhibits promiscuous coupling with various G protein subtypes including Gs, Gi/o, Gq/11, and G12/13, leading to multi-modal signal transduction. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi and Gq triggered by ETB activation. ETB coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C-terminus of Gα and intracellular loop 2 (ICL2) of ETB in ETB-Gi1 or ETB-Gq coupling. Although The C-terminus of Gα is essential for ETB-Gi1 and ETB-Gq coupling, ETB ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ETB with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ETB-induced activation.

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Section: Role Of Icl2 In Etb-gi1 or Etb-gq Couplingmentioning

confidence: 81%

Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq

Ham,

Shihoya,

Nureki

et al. 2024

Preprint

Self Cite

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show abstract

“…For this reason, structure analysis was only performed between the receptors and the α5 helix of G protein. Interestingly, the prostaglandin receptors EP2 and EP3 show different G protein coupling preferences, EP2 receptor couples to Gαs and EP3 receptor couples to Gαi 5 , 31 . The high-resolution structures of PGE 2 -bound EP2-Gαs complex (PDB 7CX2) and PGE 2 -bound EP3-Gαi complex (PDB 7WU9) have been reported 5 , 31 .…”

Section: Resultsmentioning

confidence: 99%

Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity

Lv,

Gao,

Nie

et al. 2023

Nat Commun

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Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F2α and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.

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“…Interestingly, the prostaglandin receptors EP2 and EP3 show different G protein coupling preferences, EP2 receptor couples to Gαs and EP3 receptor couples to Gαi 18,23 . The high-resolution structures of PGE2-bound EP2-Gαs complex (PDB: 7CX2) and PGE2-bound EP3-Gαi complex (PDB: 7WU9) have been reported 18,23 . We then performed structure comparison between these three structures to understand the G protein selectivity of the prostaglandin receptors.…”

Section: Molecular Mechanism Of G-protein Selectivity Of Prostaglandi...mentioning

confidence: 99%

“…For this reason, structure analysis was only performed between the receptors and the α5 helix of G protein. Interestingly, the prostaglandin receptors EP2 and EP3 show different G protein coupling preferences, EP2 receptor couples to Gαs and EP3 receptor couples to Gαi 18,23 . The high-resolution structures of PGE2-bound EP2-Gαs complex (PDB: 7CX2) and PGE2-bound EP3-Gαi complex (PDB: 7WU9) have been reported 18,23 .…”

Section: Molecular Mechanism Of G-protein Selectivity Of Prostaglandi...mentioning

confidence: 99%

FP receptor structures reveal the selectivity mechanism of prostaglandin

Liu

Lv²,

Gao

et al. 2023

Preprint

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Prostaglandins and their receptors regulate various physiological processes, such as cardiovascular homeostasis, body temperature control and female production. Carboprost, an analog of prostaglandin F2α and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH), which is a leading cause of maternal morbidity and mortality. However, off-target activation of closely related receptors such as the EP3 receptor by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. In this work, we determined two cryo-EM structures of the FP receptor bound to carboprost and latanoprost at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.

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Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex

Cited by 13 publications

References 37 publications

Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq

Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq

Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity

FP receptor structures reveal the selectivity mechanism of prostaglandin

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