Structural basis for molecular recognition at serotonin receptors

Chong Wang, Yi Jiang, Jinming Ma, Huixian Wu, Daniel Wacker, Vsevolod Katritch, Gye Won Han, Wei Liu, Xi Ping Huang, Eyal Vardy, John D. McCorvy, Xiang Gao, X. Edward Zhou, Karsten Melcher, Chenghai Zhang, Fang Bai, Huaiyu Yang, Linlin Yang, Hualiang Jiang, Bryan L. RothVadim Cherezov, Raymond C. Stevens, H. Eric Xu

Research output: Contribution to journalArticle

318 Scopus citations

Abstract

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

Original languageEnglish (US)
Pages (from-to)610-614
Number of pages5
JournalScience
Volume340
Issue number6132
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • General

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    Wang, C., Jiang, Y., Ma, J., Wu, H., Wacker, D., Katritch, V., Han, G. W., Liu, W., Huang, X. P., Vardy, E., McCorvy, J. D., Gao, X., Zhou, X. E., Melcher, K., Zhang, C., Bai, F., Yang, H., Yang, L., Jiang, H., ... Xu, H. E. (2013). Structural basis for molecular recognition at serotonin receptors. Science, 340(6132), 610-614. https://doi.org/10.1126/science.1232807