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Structural features for functional selectivity at serotonin receptors. Science 2013 May 03;340(6132):615-9

Date

03/23/2013

Pubmed ID

23519215

Pubmed Central ID

PMC3644390

DOI

10.1126/science.1232808

Scopus ID

2-s2.0-84877631485 (requires institutional sign-in at Scopus site)   583 Citations

Abstract

Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.

Author List

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC

Authors

Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
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

Amino Acid Motifs
Amino Acid Sequence
Arrestin
Arrestins
Binding Sites
Crystallography, X-Ray
Ergolines
Ergotamine
HEK293 Cells
Humans
Ligands
Lysergic Acid Diethylamide
Models, Molecular
Molecular Sequence Data
Protein Conformation
Protein Structure, Secondary
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT2B
Receptors, Serotonin
Signal Transduction
beta-Arrestins