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-Structure paper
タイトル | Structure-based design of non-hypertrophic apelin receptor modulator. |
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ジャーナル・号・ページ | Cell, Vol. 187, Issue 6, Page 1460-1475.e20, Year 2024 |
掲載日 | 2024年3月14日 |
著者 | Wei-Wei Wang / Su-Yu Ji / Wenjia Zhang / Junxia Zhang / Chenxi Cai / Rubi Hu / Shao-Kun Zang / Luwei Miao / Haomang Xu / Li-Nan Chen / Zongkuai Yang / Jia Guo / Jiao Qin / Dan-Dan Shen / Ping Liang / Yan Zhang / Yan Zhang / |
PubMed 要旨 | Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse ...Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications. |
リンク | Cell / PubMed:38428423 |
手法 | EM (単粒子) |
解像度 | 2.6 - 3.2 Å |
構造データ | EMDB-38794, PDB-8xzf: EMDB-38795, PDB-8xzg: EMDB-38796, PDB-8xzh: EMDB-38797, PDB-8xzi: EMDB-38798, PDB-8xzj: |
化合物 | PDB-1d5n: |
由来 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / APLNR / Class A GPCR / Synthetic peptide (ペプチド合成) / apelin / Structural protein (タンパク質) / MM07 / Cyclic peptide (環状ペプチド) / CMF-019 / G-protein-biased small molecule agonist |