9UY3

Anamorelin bound growth hormone secretagogue receptor in complex with Gq

This is a non-PDB format compatible entry.

Summary for 9UY3

• Entry DOI: 10.2210/pdb9uy3/pdb
• EMDB information: 64606
• Descriptor: Engineered G-alpha-q subunit, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: growth hormone secretagogue receptor, ghsr, anamorelin, ghrelin receptor, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 182756.48

Authors

Wang, R.,Sun, J.,Liu, H.,Guo, S.,Zhang, Y.,Hu, W.,Wang, J.,Liu, H.,Zhuang, Y.,Jiang, Y.,Xie, X.,Xu, H.E.,Wang, Y. (deposition date: 2025-05-14, release date: 2025-07-02)

Primary citation

Wang, R.L.,Sun, J.,Liu, H.,Guo, S.M.,Zhang, Y.,Hu, W.,Wang, J.,Liu, H.,Zhuang, Y.W.,Jiang, Y.,Xie, X.,Xu, H.E.,Wang, Y.
Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor.
Acta Pharmacol.Sin., 2025

PubMed 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 G 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 E124 and R283. 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.

PubMed: 40542284
DOI: 10.1038/s41401-025-01606-7

Experimental method

ELECTRON MICROSCOPY (2.52 Å)