Structures of human prostaglandin F(2α) receptor reveal the mechanism of ligand and G protein selectivity.
Structures of human prostaglandin F(2α) receptor reveal the mechanism of ligand and G protein selectivity.
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DOI：
10.1038/s41467-023-43922-8
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发表时间：
2023-12-08
影响因子：
16.6
通讯作者：
Liu, Xiangyu
中科院分区：
文献类型：
--
作者：
Lv, Xiuqing;Gao, Kaixuan;Nie, Jia;Zhang, Xin;Zhang, Shuhao;Ren, Yinhang;Sun, Xiaoou;Li, Qi;Huang, Jingrui;Liu, Lijuan;Zhang, Xiaowen;Zhang, Weishe;Liu, Xiangyu
前列腺素及其受体调节各种生理过程。卡前列素是前列腺素F2α的类似物和前列腺素F2-α受体（FP受体）的激动剂，临床上用于治疗产后出血（PPH）。然而，卡前列素对密切相关的受体如前列腺素E受体亚型EP 3（EP 3受体）的脱靶激活导致副作用并限制了临床应用。同时，FP受体选择性激动剂拉坦前列素由于其溶解度差和清除快而不适合治疗PPH。在这里，我们提出了两个冷冻电镜结构的FP受体结合卡前列素和拉坦前列素-FA（游离酸形式的拉坦前列素）在2.7毫米和3.2毫米的分辨率，分别。这些结构揭示了FP受体对内源性前列腺素和临床药物的选择性的分子机制，以及前列腺素受体对G蛋白偶联偏好的分子机制。这些结构信息可能指导更好的前列腺素药物的开发。Cryo-EM结构揭示了前列腺素F2α受体的配体和G蛋白选择性的分子机制，为开发更好的产后出血药物提供指导。
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. Cryo-EM structures reveal the molecular mechanism of ligands and G protein selectivity for prostaglandin F2α receptor, providing guidance for development of better postpartum hemorrhage drugs.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
14.9
作者：
Kooistra AJ;Mordalski S;Pándy-Szekeres G;Esguerra M;Mamyrbekov A;Munk C;Keserű GM;Gloriam DE
通讯作者：
Gloriam DE
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/s1388-1981(99)00164-x
发表时间：
2000-01-17
影响因子：
4.8
作者：
Abramovitz, M;Adam, M;Metters, KM
通讯作者：
Metters, KM