Structural insights into the extracellular recognition of the human serotonin 2B receptor by an antibody

Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8223-8228. doi: 10.1073/pnas.1700891114. Epub 2017 Jul 17.


Monoclonal antibodies provide an attractive alternative to small-molecule therapies for a wide range of diseases. Given the importance of G protein-coupled receptors (GPCRs) as pharmaceutical targets, there has been an immense interest in developing therapeutic monoclonal antibodies that act on GPCRs. Here we present the 3.0-Å resolution structure of a complex between the human 5-hydroxytryptamine 2B (5-HT2B) receptor and an antibody Fab fragment bound to the extracellular side of the receptor, determined by serial femtosecond crystallography with an X-ray free-electron laser. The antibody binds to a 3D epitope of the receptor that includes all three extracellular loops. The 5-HT2B receptor is captured in a well-defined active-like state, most likely stabilized by the crystal lattice. The structure of the complex sheds light on the mechanism of selectivity in extracellular recognition of GPCRs by monoclonal antibodies.

Keywords: GPCR; X-ray free-electron laser; active state; antibody recognition; serial femtosecond crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / metabolism
  • Binding, Competitive
  • Catalytic Domain
  • Crystallography, X-Ray
  • Epitopes / chemistry
  • Epitopes / metabolism
  • Ergotamine / chemistry
  • Ergotamine / metabolism
  • Humans
  • Immunoglobulin Fab Fragments / chemistry*
  • Immunoglobulin Fab Fragments / metabolism
  • Models, Molecular
  • Protein Conformation
  • Receptor, Serotonin, 5-HT2B / chemistry*
  • Receptor, Serotonin, 5-HT2B / immunology*
  • Receptor, Serotonin, 5-HT2B / metabolism
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / metabolism


  • Antibodies, Monoclonal
  • Epitopes
  • Immunoglobulin Fab Fragments
  • Receptor, Serotonin, 5-HT2B
  • Serotonin Receptor Agonists
  • Ergotamine

Associated data

  • PDB/5TUD