@article{a1e918bf75964fc5a1345d65e9f63f20,
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. Understanding how one drug can bind to many similar targets and have different functional outcomes will inform drug design with desired efficacy profiles.",
keywords = "GPCR, crystal structures, ergotamine, polypharmacology, ritanserin, selectivity, serotonin 2C receptor",
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 Huang, {Xi Ping} 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 Liu, {Zhi Jie}",
note = "Funding Information: This work was supported by grants from the Ministry of Science and Technology of China (2014CB910400 and 2015CB910104), the National Nature Science Foundation of China (31330019) (to Z.J.L.), the NIH (R01MH112205 and U19MH82441), the Michael Hooker Distinguished Professorship, the NIMH Psychoactive Drug Screening Program (271201300017C-4-01) (to B.L.R., J.M., and others from the Roth lab), the NIH (U54GM094618) (to V.K.), the Russian Science Foundation (16-14-10273) (to P.P.), and the Lundbeck Foundation (R163-2013-16327) (to D.E.G.). We thank the Shanghai Municipal Government and ShanghaiTech University for financial support. The diffraction data were collected at the BL41XU of SPring-8 (JASRI proposal 2015B1031 and 2016A2731), GM/CA at APS of Argonne National Lab, and X06SA beamline at the Swiss Light Source of the Paul Scherrer Institute. We thank K. Hasegawa, H. Okumura, H. Murakami, M. Audet, M. Wang, C. Huang, and V. Olieric for their help with data collection. We thank the Cloning, Cell Expression, Assay, and Protein Purification Core Facilities of iHuman Institute for their support. We thank I. Wilson for careful review and insightful discussions on the manuscript; A. Walker for assistance with the manuscript; and T. Hua, V. Cherezov, T. Tsonkov, G. Song, W. Shui, D. Liu, H. Tao, G. Zhong, F. Xu, B. Wu, Q. Zhao, and W. Liu for helpful discussions. Funding Information: This work was supported by grants from the Ministry of Science and Technology of China ( 2014CB910400 and 2015CB910104 ), the National Nature Science Foundation of China ( 31330019 ) (to Z.J.L.), the NIH ( R01MH112205 and U19MH82441 ), the Michael Hooker Distinguished Professorship , the NIMH Psychoactive Drug Screening Program ( 271201300017C-4-01 ) (to B.L.R., J.M., and others from the Roth lab), the NIH ( U54GM094618 ) (to V.K.), the Russian Science Foundation ( 16-14-10273 ) (to P.P.), and the Lundbeck Foundation ( R163-2013-16327 ) (to D.E.G.). We thank the Shanghai Municipal Government and ShanghaiTech University for financial support. The diffraction data were collected at the BL41XU of SPring-8 (JASRI proposal 2015B1031 and 2016A2731 ), GM/CA at APS of Argonne National Lab, and X06SA beamline at the Swiss Light Source of the Paul Scherrer Institute. We thank K. Hasegawa, H. Okumura, H. Murakami, M. Audet, M. Wang, C. Huang, and V. Olieric for their help with data collection. We thank the Cloning, Cell Expression, Assay, and Protein Purification Core Facilities of iHuman Institute for their support. We thank I. Wilson for careful review and insightful discussions on the manuscript; A. Walker for assistance with the manuscript; and T. Hua, V. Cherezov, T. Tsonkov, G. Song, W. Shui, D. Liu, H. Tao, G. Zhong, F. Xu, B. Wu, Q. Zhao, and W. Liu for helpful discussions. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = feb,
day = "8",
doi = "10.1016/j.cell.2018.01.001",
language = "English",
volume = "172",
pages = "719--730.e14",
journal = "Cell",
issn = "0092-8674",
number = "4",
}