Structural insights into the extracellular recognition of the human serotonin 2B receptor by an antibody. Proc Natl Acad Sci U S A 2017 Aug 01;114(31):8223-8228
Date
07/19/2017Pubmed ID
28716900Pubmed Central ID
PMC5547598DOI
10.1073/pnas.1700891114Scopus ID
2-s2.0-85026770347 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
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.
Author List
Ishchenko A, Wacker D, Kapoor M, Zhang A, Han GW, Basu S, Patel N, Messerschmidt M, Weierstall U, Liu W, Katritch V, Roth BL, Stevens RC, Cherezov VAuthor
Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibodies, MonoclonalBinding, Competitive
Catalytic Domain
Crystallography, X-Ray
Epitopes
Ergotamine
Humans
Immunoglobulin Fab Fragments
Models, Molecular
Protein Conformation
Receptor, Serotonin, 5-HT2B
Serotonin Receptor Agonists
