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

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

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 Å and 2.52 Å, 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.

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Fig. 1: Cryo-EM structures of the Gq-coupled GHSR bound to Macimorelin and Anamorelin.
Fig. 2: Molecular recognition of Macimorelin and Anamorelin by GHSR.
Fig. 3: Dual functional profiling of GHSR mutants on Macimorelin- and Anamorelin-induced response.
Fig. 4: Comparisons of multi-state GHSR.
Fig. 5: G protein coupling of GHSR.

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Acknowledgements

The cryo-electron microscopy data were collected at the Shanghai Advanced Center for Electron Microscopy, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. We thank Wen Hu for performing data collection. This work was supported by the National Natural Science Foundation of China (32171187 to YJ, 32130022 to HEX, 82121005 to XX, and HEX, 82330113 to XX, 82304579 to SMG); the National Key R&D Program of China (2022YFC2703105 to HEX); CAS Strategic Priority Research Program (XDB37030103 to HEX); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to HEX); State Key Laboratory of Drug Research, Grant No. SKLDR-2024-TT-02 (XX and HL); the Lingang Laboratory, Grant No. LG-GG-202204-01 (HEX); the Special Research Assistant Project of Chinese Academy of Sciences (to YW).

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Author notes

  1. These authors contributed equally: Ruo-lan Wang, Jun Sun, Heng Liu, Shi-meng Guo

Authors and Affiliations

  1. CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ruo-lan Wang, Heng Liu, Shi-meng Guo, Yu Zhang, Wen Hu, Jiang Wang, Hong Liu, Xin Xie, H. Eric Xu & Yue Wang

  2. University of Chinese Academy of Sciences, Beijing, 101408, China

    Ruo-lan Wang, Hong Liu, Xin Xie & H. Eric Xu

  3. School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China

    Jun Sun & Xin Xie

  4. Lingang Laboratory, Shanghai, 200031, China

    Yu Zhang, Jiang Wang & Yi Jiang

  5. The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen Hu

  6. Medicinal Bioinformatics Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    You-wen Zhuang

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  1. Ruo-lan Wang
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Contributions

YW, HEX, and XX initiated the project. RLW expressed, optimized and purified the receptor complex. HL performed cryo-EM grid preparation, data acquisition, structure determination and model building. WH performed cryo-EM data acquisition. JS and SMG performed cell-based binding and functional assays under the supervision of XX. YZ synthesized Macimorelin and Anamorelin under the supervision of JW and HL. YW and RLW prepared the figures and wrote the draft; YWZ and YJ participated in project guidance. YW, HEX, and XX wrote the manuscript with inputs from the authors.

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Correspondence to Xin Xie, H. Eric Xu or Yue Wang.

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HEX is a founder of Cascade Pharmaceutics. All the other authors declare no other competing interests.

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Wang, Rl., Sun, J., Liu, H. et al. Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01606-7

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