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Cell Discov. 2018 Mar 13;4:12. doi: 10.1038/s41421-018-0009-2. eCollection 2018.

Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist.

Yin W1,2,3,4, Zhou XE1,4, Yang D3,5, de Waal PW4, Wang M6, Dai A3,5, Cai X3,5, Huang CY6, Liu P1, Wang X1, Yin Y1,4, Liu B1, Zhou Y7, Wang J7, Liu H7, Caffrey M8, Melcher K4, Xu Y3, Wang MW3,5,9,10, Xu HE1,4, Jiang Y1,4.

Author information

1VARI-SIMM Center, Center for Structure and Function of Drug Targets, The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 China.
2University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing, 100049 China.
3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
4Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503 USA.
5The National Center for Drug Screening, Shanghai, 201203 China.
6Swiss Light Source, Paul Scherrer Institute, Villigen, 5232 Switzerland.
7State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, 201203 China.
8Membrane Structural and Functional Biology Group, Schools of Medicine and Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
9School of Pharmacy, Fudan University, Shanghai, 201203 China.
10School of Life Science and Technology, ShanghaiTech University, Pudong, Shanghai 201203 China.


5-hydroxytryptamine (5-HT, also known as serotonin) regulates many physiological processes through the 5-HT receptor family. Here we report the crystal structure of 5-HT1B subtype receptor (5-HT1BR) bound to the psychotropic serotonin receptor inverse agonist methiothepin (MT). Crystallization was facilitated by replacing ICL3 with a novel optimized variant of BRIL (OB1) that enhances the formation of intermolecular polar interactions, making OB1 a potential useful tool for structural studies of membrane proteins. Unlike the agonist ergotamine (ERG), MT occupies only the conserved orthosteric binding pocket, explaining the wide spectrum effect of MT on serotonin receptors. Compared with ERG, MT shifts toward TM6 and sterically pushes residues W3276.48, F3306.50 and F3316.51 from inside the orthosteric binding pocket, leading to an outward movement of the extracellular end and a corresponding inward shift of the intracellular end of TM6, a feature shared by other reported inactive G protein-coupled receptor (GPCR) structures. Together with the previous agonist-bound serotonin receptor structures, the inverse agonist-bound 5-HT1BR structure identifies a basis for the ligand-mediated switch of 5-HT1BR activity and provides a structural understanding of the inactivation mechanism of 5-HT1BR and some other class A GPCRs, characterized by ligand-induced outward movement of the extracellular end of TM6 that is coupled with inward movement of the cytoplasmic end of this helix.

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