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TitleMolecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor.
Journal, issue, pagesActa Pharmacol Sin, Vol. 46, Issue 11, Page 2998-3008, Year 2025
Publish dateJun 20, 2025
AuthorsRuo-Lan Wang / Jun Sun / Heng Liu / Shi-Meng Guo / Yu Zhang / Wen Hu / Jiang Wang / Hong Liu / You-Wen Zhuang / Yi Jiang / Xin Xie / H Eric Xu / Yue Wang /
PubMed AbstractThe 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 ...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.
External linksActa Pharmacol Sin / PubMed:40542284 / PubMed Central
MethodsEM (single particle)
Resolution2.52 - 2.63 Å
Structure data

64606

9uy3

EMDB-64606, PDB-9uy3:
Anamorelin bound growth hormone secretagogue receptor in complex with Gq
Method: EM (single particle) / Resolution: 2.52 Å

64734

9v2n

EMDB-64734, PDB-9v2n:
Macimorelin bound growth hormone secretagogue receptor in complex with Gq
Method: EM (single particle) / Resolution: 2.63 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

PDB-1esd:
THE MOLECULAR MECHANISM OF ENANTIORECOGNITION BY ESTERASES

PDB-1eqv:
SIMPLIFICATION OF A PROTEIN LOOP IN STAPHYLOCOCCAL NUCLEASE

Source
  • homo sapiens (human)
  • lama glama (llama)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / growth hormone secretagogue receptor / GHSR / Anamorelin / ghrelin receptor / MEMBRANE PROTEIN/IMMUNE SYSTEM / Macimorelin / GPCR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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