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

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

  • Yin W 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.
  • Zhou XE 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.
  • Yang D 3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
  • de Waal PW 4Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503 USA.
  • Wang M 6Swiss Light Source, Paul Scherrer Institute, Villigen, 5232 Switzerland.
  • Dai A 3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
  • Cai X 3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
  • Huang CY 6Swiss Light Source, Paul Scherrer Institute, Villigen, 5232 Switzerland.
  • Liu P 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.
  • Wang X 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.
  • Yin Y 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.
  • Liu B 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.
  • Zhou Y 7State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, 201203 China.
  • Wang J 7State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, 201203 China.
  • Liu H 7State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, 201203 China.
  • Caffrey M 8Membrane Structural and Functional Biology Group, Schools of Medicine and Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
  • Melcher K 4Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503 USA.
  • Xu Y 3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
  • Wang MW 3The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203 China.
  • Xu HE 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.
  • Jiang Y 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.
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  • 2018-03-22
Published in:
  • Cell discovery. - 2018
English 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.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/278569
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