4.5 Article

Inactive and active state structures template selective tools for the human 5-HT5A receptor

期刊

NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 7, 页码 677-+

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NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00796-6

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资金

  1. US National Institutes of Health [RO1MH112205, U24DK1169195, R35GM122481]
  2. National Institutes of Health SIG [1S10OD025132, 1S10OD028504]
  3. Cancer Center Core Support Grant [P30 CA016086]
  4. National Cancer Institute [ACB-12002]
  5. National Institute of General Medical Sciences [AGM-12006]
  6. Department of Energy Office of Science [DE-AC02-06CH11357]
  7. Schrodinger

向作者/读者索取更多资源

This comprehensive study investigates the enigmatic serotonin receptor 5-HT5AR, including its pharmacological investigations and structures in different states. A highly selective and potent antagonist for 5-HT5AR was developed, and this study provides insights for structure-based drug discovery.
This comprehensive study of the most enigmatic serotonin receptor 5-HT5AR includes lots of pharmacological investigations, inactive and active state structures with antagonist, partial agonist and full agonists. Also, a highly potent and selective antagonist was developed. Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT)(5A) receptor (5-HT5AR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 angstrom) structures of human 5-HT(5A)Rs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HT5AR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HT5AR.

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