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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. / Peng, Yao; McCorvy, John D.; Harpsøe, Kasper; Lansu, Katherine; Yuan, Shuguang; Popov, Petr; Qu, Lu; Pu, Mengchen; Che, Tao; Nikolajsen, Louise F.; Huang, Xi-ping; Wu, Yiran; Shen, Ling; Bjørn-Yoshimoto, Walden E.; Ding, Kang; Wacker, Daniel; Han, Gye Won; Cheng, Jianjun; Katritch, Vsevolod; Jensen, Anders A.; Hanson, Michael A.; Zhao, Suwen; Gloriam, David E.; Roth, Bryan L.; Stevens, Raymond C.; Liu, Zhi-jie.

In: Cell, Vol. 172, No. 4, P719-730.E14, 2018, p. 719-730.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

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

APA

Peng, Y., McCorvy, J. D., Harpsøe, K., Lansu, K., Yuan, S., Popov, P., ... 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

Vancouver

Peng Y, McCorvy JD, Harpsøe K, Lansu K, Yuan S, Popov P et al. 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell. 2018;172(4):719-730. P719-730.E14. https://doi.org/10.1016/j.cell.2018.01.001

Author

Peng, Yao ; McCorvy, John D. ; Harpsøe, Kasper ; Lansu, Katherine ; Yuan, Shuguang ; Popov, Petr ; Qu, Lu ; Pu, Mengchen ; Che, Tao ; Nikolajsen, Louise F. ; Huang, Xi-ping ; Wu, Yiran ; Shen, Ling ; Bjørn-Yoshimoto, Walden E. ; Ding, Kang ; Wacker, Daniel ; Han, Gye Won ; Cheng, Jianjun ; Katritch, Vsevolod ; Jensen, Anders A. ; Hanson, Michael A. ; Zhao, Suwen ; Gloriam, David E. ; Roth, Bryan L. ; Stevens, Raymond C. ; Liu, Zhi-jie. / 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. In: Cell. 2018 ; Vol. 172, No. 4. pp. 719-730.

Bibtex

@article{b26952c6d00443d581a4d5d50f20b72b,
title = "5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology",
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.",
keywords = "The Faculty of Health and Medical Sciences, GPCR, Serotonin 2C receptor, ergotamine, ritanserin, polypharmacology, selectivity, crystal structures",
author = "Yao Peng and McCorvy, {John D.} and Kasper Harps{\o}e and Katherine Lansu and Shuguang Yuan and Petr Popov and Lu Qu and Mengchen Pu and Tao Che and Nikolajsen, {Louise F.} and Xi-ping Huang and Yiran Wu and Ling Shen and Bj{\o}rn-Yoshimoto, {Walden E.} and Kang Ding and Daniel Wacker and Han, {Gye Won} and Jianjun Cheng and Vsevolod Katritch and Jensen, {Anders A.} and Hanson, {Michael A.} and Suwen Zhao and Gloriam, {David E.} and Roth, {Bryan L.} and Stevens, {Raymond C.} and Zhi-jie Liu",
year = "2018",
doi = "10.1016/j.cell.2018.01.001",
language = "English",
volume = "172",
pages = "719--730",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

AU - Peng, Yao

AU - McCorvy, John D.

AU - Harpsøe, Kasper

AU - Lansu, Katherine

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

PY - 2018

Y1 - 2018

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.

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.

KW - The Faculty of Health and Medical Sciences

KW - GPCR

KW - Serotonin 2C receptor

KW - ergotamine

KW - ritanserin

KW - polypharmacology

KW - selectivity

KW - crystal structures

U2 - 10.1016/j.cell.2018.01.001

DO - 10.1016/j.cell.2018.01.001

M3 - Journal article

VL - 172

SP - 719

EP - 730

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

M1 - P719-730.E14

ER -

ID: 189253364