National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
RO1MH112205
米国
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
U24DK1169195
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2022 タイトル: Inactive and active state structures template selective tools for the human 5-HT receptor. 著者: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F ...著者: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F Fay / Bryan L Roth / 要旨: 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 ...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) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, 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-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.