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Science 340 (6132): 610-614

Copyright © 2013 by the American Association for the Advancement of Science

Structural Basis for Molecular Recognition at Serotonin Receptors

Chong Wang,1,* Yi Jiang,1,2,* Jinming Ma,1,3,* Huixian Wu,1 Daniel Wacker,1 Vsevolod Katritch,1 Gye Won Han,1 Wei Liu,1 Xi-Ping Huang,4 Eyal Vardy,4 John D. McCorvy,4 Xiang Gao,3 X. Edward Zhou,3 Karsten Melcher,3 Chenghai Zhang,2,3 Fang Bai,5 Huaiyu Yang,6 Linlin Yang,6 Hualiang Jiang,6 Bryan L. Roth,4 Vadim Cherezov,1 Raymond C. Stevens,1,{dagger} H. Eric Xu2,3,{dagger}

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.

1 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Van Andel Research Institute/Shanghai Institute of Materia Medica Center, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3 Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA.
4 National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27599, USA.
5 Department of Engineering Mechanics, State Key Laboratory of Technology, Faculty of Chemical, Environmental, and Biological Science and Technology, Dalian University of Technology, Dalian 116023, China.
6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

* These authors contributed equally to this work.

{dagger} Corresponding author. E-mail: eric.xu{at} (H.E.X); stevens{at} (R.C.S.)

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