Structural Basis for Molecular Recognition at Serotonin Receptors

Overview

Journal Science

Specialty Science

Date 2013 Mar 23

PMID 23519210

Citations 201

Authors

Chong Wang

Yi Jiang

Jinming Ma

Huixian Wu

Daniel Wacker

Vsevolod Katritch

Gye Won Han

Wei Liu

Xi-Ping Huang

Eyal Vardy

John D McCorvy

Xiang Gao

X Edward Zhou

Karsten Melcher

Chenghai Zhang

Fang Bai

Huaiyu Yang

Linlin Yang

Hualiang Jiang

Bryan L Roth

Vadim Cherezov

Raymond C Stevens

H Eric Xu

Affiliations

Soon will be listed here.

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.

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