Faculty Collaboration Database

Structural basis for molecular recognition at serotonin receptors. Science 2013 May 03;340(6132):610-4

Date

03/23/2013

Pubmed ID

23519210

Pubmed Central ID

PMC3644373

DOI

10.1126/science.1232807

Scopus ID

2-s2.0-84877607189 (requires institutional sign-in at Scopus site)   426 Citations

Abstract

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

Author List

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE

Authors

Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
John McCorvy PhD Assistant 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 Sequence
Binding Sites
Crystallography, X-Ray
Dihydroergotamine
Ergotamine
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Ligands
Lysergic Acid Diethylamide
Models, Molecular
Molecular Docking Simulation
Molecular Sequence Data
Mutagenesis
Norfenfluramine
Pindolol
Propranolol
Protein Conformation
Protein Folding
Protein Structure, Secondary
Receptor, Serotonin, 5-HT1B
Serotonin 5-HT1 Receptor Agonists
Tryptamines