5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
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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 journal › Journal article › Research › peer-review
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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 - 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
C2 - 29398112
VL - 172
SP - 719
EP - 730
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
M1 - P719-730.E14
ER -
ID: 189253364