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Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor

文献类型：期刊论文

作者Wang, Ruo-lan5,6; Sun, Jun4; Liu, Heng6; Guo, Shi-meng6; Zhang, Yu3,6; Hu, Wen2,6; Wang, Jiang3,6; Liu, Hong5,6; Zhuang, You-wen1; Jiang, Yi3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-06-20
页码11
关键词growth hormone secretagogue receptor anamorelin macimorelin molecular recognition
ISSN号1671-4083
DOI10.1038/s41401-025-01606-7
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Wang, Yue(wangyue1@simm.ac.cn)
英文摘要The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition is essential for developing therapeutic interventions. In this study, we investigated the molecular recognition mechanisms of two clinically approved drugs: Macimorelin (used for diagnosing adult growth hormone deficiency) and Anamorelin (approved in Japan for cancer cachexia). Using high-resolution cryo-electron microscopy, we determined the structures of GHSR bound to Macimorelin and Anamorelin in complex with Gq proteins at resolutions of 2.63 & Aring; and 2.52 & Aring;, respectively. We revealed that both drugs occupied a bifurcated binding pocket divided by a conserved salt bridge between E1243.33 and R2836.55. Through systematic mutagenesis and functional studies, we identified the key residues underlying the higher binding affinity of Anamorelin compared to Macimorelin. In addition, structural comparison of GHSR in complex with different G protein subtypes elucidated the mechanisms driving G protein selectivity. Our results provide crucial insights into GHSR-drug interactions and offer valuable guidance for designing more selective and potent GHSR agonists.
WOS关键词CANCER CACHEXIA ; DOUBLE-BLIND ; GHRELIN ; DIAGNOSIS ; STIMULATION ; ASSOCIATION ; DEFICIENCY ; GENE
资助项目Chinese Academy of Sciences ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82330113] ; National Natural Science Foundation of China[82304579] ; National Key R&D Program of China[2022YFC2703105] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; State Key Laboratory of Drug Research[SKLDR-2024-TT-02] ; Lingang Laboratory[LG-GG-202204-01] ; Special Research Assistant Project of Chinese Academy of Sciences
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001512255000001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/318627]  
专题中国科学院上海药物研究所
通讯作者Xie, Xin; Xu, H. Eric; Wang, Yue
作者单位1.Shanghai Jiao Tong Univ, Med Bioinformat Ctr, Sch Med, Shanghai 200025, Peoples R China
2.Chinese Acad Sci, Shanghai Adv Electron Microscope Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Lingang Lab, Shanghai 200031, Peoples R China
4.Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China
5.Univ Chinese Acad Sci, Beijing 101408, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Ruo-lan,Sun, Jun,Liu, Heng,et al. Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor[J]. ACTA PHARMACOLOGICA SINICA,2025:11.
APA Wang, Ruo-lan.,Sun, Jun.,Liu, Heng.,Guo, Shi-meng.,Zhang, Yu.,...&Wang, Yue.(2025).Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor.ACTA PHARMACOLOGICA SINICA,11.
MLA Wang, Ruo-lan,et al."Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor".ACTA PHARMACOLOGICA SINICA (2025):11.

入库方式： OAI收割

来源：上海药物研究所

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