TY - JOUR
T1 - Structural determinants of 5-HT2B receptor activation and biased agonism
AU - McCorvy, John D.
AU - Wacker, Daniel
AU - Wang, Sheng
AU - Agegnehu, Bemnat
AU - Liu, Jing
AU - Lansu, Katherine
AU - Tribo, Alexandra R.
AU - Olsen, Reid H.J.
AU - Che, Tao
AU - Jin, Jian
AU - Roth, Bryan L.
N1 - Funding Information:
We thank R. Axel (Columbia University) for the HTLA cells expressing TEV-fused β-arrestin2 and R. Fischetti and the staff of APS GM/CA for assistance in the development and use of the minibeam and beam time at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. Use of the Advanced Photon Source was supported by the Office of Science of the US Department of Energy. This work was supported by US National Institutes of Health (NIH) grants R01MH61887 (B.L.R.), R01NS100930 (J.J.), U19MH82441 (J.J. and B.L.R.) and F31-NS093917 (R.H.J.O.), the NIMH Psychoactive Drug Screening Program Contract (B.L.R.) and the Michael Hooker Distinguished Chair of Pharmacology (B.L.R.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor—the human 5-HT2B receptor—in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.
AB - Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor—the human 5-HT2B receptor—in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.
UR - https://www.scopus.com/pages/publications/85052592263
U2 - 10.1038/s41594-018-0116-7
DO - 10.1038/s41594-018-0116-7
M3 - Article
C2 - 30127358
AN - SCOPUS:85052592263
SN - 1545-9993
VL - 25
SP - 787
EP - 796
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 9
ER -