Download Mendeley5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.
Peng, Y., McCorvy, J.D., Harpsoe, K., Lansu, K., Yuan, S., Popov, P., Qu, L., Pu, M., Che, T., Nikolajsen, L.F., Huang, X.P., Wu, Y., Shen, L., Bjorn-Yoshimoto, W.E., Ding, K., Wacker, D., Han, G.W., Cheng, J., Katritch, V., Jensen, A.A., Hanson, M.A., Zhao, S., Gloriam, D.E., Roth, B.L., Stevens, R.C., Liu, Z.J.(2018) Cell 172: 719-730.e14
- PubMed: 29398112
- DOI: https://doi.org/10.1016/j.cell.2018.01.001
- Primary Citation of Related Structures:
6BQG, 6BQH - PubMed 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?? and 2.7??, 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.
Organizational Affiliation:
iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
