6BQG

Crystal structure of 5-HT2C in complex with ergotamine

Summary for 6BQG

• Entry DOI: 10.2210/pdb6bqg/pdb
• Descriptor: 5-hydroxytryptamine receptor 2C,Soluble cytochrome b562, Ergotamine, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate (3 entities in total)
• Functional Keywords: human 5-ht2c receptor, gpcr, ergotamine, polypharmacology, bril, lcp, membrane protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P28335
• Total number of polymer chains: 1
• Total formula weight: 52248.26

Authors

Peng, Y.,McCorvy, J.D.,Harpsoe, K.,Lansu, K.,Yuan, S.,Popov, P.,Qu, L.,Pu, M.,Che, T.,Nikolajse, 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. (deposition date: 2017-11-27, release date: 2018-02-14, Last modification date: 2024-10-30)

Primary citation

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.
5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.
Cell, 172:719-730.e14, 2018

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 receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT 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 receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT 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.

PubMed: 29398112
DOI: 10.1016/j.cell.2018.01.001

Experimental method

X-RAY DIFFRACTION (3 Å)