Faculty Collaboration Database

Structural determinants of 5-HT_2B receptor activation and biased agonism. Nat Struct Mol Biol 2018 Sep;25(9):787-796

Date

08/22/2018

Pubmed ID

30127358

Pubmed Central ID

PMC6237183

DOI

10.1038/s41594-018-0116-7

Scopus ID

2-s2.0-85052592263 (requires institutional sign-in at Scopus site)   131 Citations

Abstract

Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT_2B receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.

Author List

McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo AR, Olsen RHJ, Che T, Jin J, Roth BL

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Binding Sites
Humans
Ligands
Mutagenesis
Protein Conformation
Receptor, Serotonin, 5-HT2B
Serotonin Receptor Agonists
Signal Transduction