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

Andrii Ishchenko, Daniel Wacker, Mili Kapoor, Ai Zhang, Gye Won Han, Shibom Basu, Nilkanth Patel, Marc Messerschmidt, Uwe Weierstall, Wei Liu, Vsevolod Katritch, Bryan L. Roth, Raymond C. Stevens, Vadim Cherezov

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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-hydroxy-tryptamine 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.

Original languageEnglish (US)
Pages (from-to)8223-8228
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number31
DOIs
StatePublished - Aug 1 2017

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Keywords

  • Active state
  • Antibody recognition
  • GPCR
  • Serial femtosecond crystallography
  • X-ray free-electron laser

ASJC Scopus subject areas

  • General

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