5-HT2C  Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

Yao Peng; John D. McCorvy; Kasper Harpsøe; Katherine Lansu; Shuguang Yuan; Petr Popov; Lu Qu; Mengchen Pu; Tao Che; Louise F. Nikolajsen; Xi-ping Huang; Yiran Wu; Ling Shen; Walden E. Bjørn-Yoshimoto; Kang Ding; Daniel Wacker; Gye Won Han; Jianjun Cheng; Vsevolod Katritch; Anders A. Jensen; Michael A. Hanson; Suwen Zhao; David E. Gloriam; Bryan L. Roth; Raymond C. Stevens; Zhi-jie Liu

doi:10.1016/j.cell.2018.01.001

5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

Yao Peng, John D. McCorvy, Kasper Harpsøe, Katherine Lansu, Shuguang Yuan, Petr Popov, Lu Qu, Mengchen Pu, Tao Che, Louise F. Nikolajsen, Xi-ping Huang, Yiran Wu, Ling Shen, Walden E. Bjørn-Yoshimoto, Kang Ding, Daniel Wacker, Gye Won Han, Jianjun Cheng, Vsevolod Katritch, Anders A. JensenMichael A. Hanson, Suwen Zhao, David E. Gloriam, Bryan L. Roth, Raymond C. Stevens, Zhi-jie Liu

93 Citations (Scopus)

Abstract

Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT_2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT_2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT_2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT_2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.

Original language	English
Article number	P719-730.E14
Journal	Cell
Volume	172
Issue number	4
Pages (from-to)	719-730
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2018.01.001
Publication status	Published - 8 Feb 2018

Keywords

Faculty of Health and Medical Sciences
GPCR
Serotonin 2C receptor
ergotamine
ritanserin
polypharmacology
selectivity
crystal structures

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Peng, Y., McCorvy, J. D., Harpsøe, K., Lansu, K., Yuan, S., Popov, P., Qu, L., Pu, M., Che, T., Nikolajsen, L. F., Huang, X., Wu, Y., Shen, L., Bjørn-Yoshimoto, W. E., Ding, K., Wacker, D., Han, G. W., Cheng, J., Katritch, V., ... Liu, Z. (2018). 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell, 172(4), 719-730. [P719-730.E14]. https://doi.org/10.1016/j.cell.2018.01.001

Peng, Y, McCorvy, JD, Harpsøe, K, Lansu, K, Yuan, S, Popov, P, Qu, L, Pu, M, Che, T, Nikolajsen, LF, Huang, X, Wu, Y, Shen, L, Bjørn-Yoshimoto, WE, Ding, K, Wacker, D, Han, GW, Cheng, J, Katritch, V, Jensen, AA, Hanson, MA, Zhao, S, Gloriam, DE, Roth, BL, Stevens, RC & Liu, Z 2018, '5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology', Cell, vol. 172, no. 4, P719-730.E14, pp. 719-730. https://doi.org/10.1016/j.cell.2018.01.001

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abstract = "Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 {\AA} and 2.7 {\AA}, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.",

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AU - Yuan, Shuguang

AU - Popov, Petr

AU - Qu, Lu

AU - Pu, Mengchen

AU - Che, Tao

AU - Nikolajsen, Louise F.

AU - Huang, Xi-ping

AU - Wu, Yiran

AU - Shen, Ling

AU - Bjørn-Yoshimoto, Walden E.

AU - Ding, Kang

AU - Wacker, Daniel

AU - Han, Gye Won

AU - Cheng, Jianjun

AU - Katritch, Vsevolod

AU - Jensen, Anders A.

AU - Hanson, Michael A.

AU - Zhao, Suwen

AU - Gloriam, David E.

AU - Roth, Bryan L.

AU - Stevens, Raymond C.

AU - Liu, Zhi-jie

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N2 - Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.

AB - Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.

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