scholarly journals Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT1F-G protein complex

2021 ◽  
Author(s):  
Sijie Huang ◽  
peiyu Xu ◽  
Yangxia Tan ◽  
Chongzhao You ◽  
Yumu Zhang ◽  
...  
Keyword(s):  
G Protein ◽  
Serotonin Receptors ◽  
Migraine Headache ◽  
Rational Design ◽  
Serotonin Receptor ◽  
Structural Basis ◽  
Selective Activation ◽  
Inhibitory G Protein ◽  
New Generation ◽  
Anti Migraine Drug

Migraine headache has become global pandemics and is the number one reason of work day loss. The most common drugs for anti-migraine are the triptan class of drugs that are agonists for serotonin receptors 5-HT1B and 5-HT1D. However, these drugs have side effects related to vasoconstriction that could have fatal consequences of ischemic heart disease and myocardial infarction. Lasmiditan is a new generation of anti-migraine drug that selectively binds to the serotonin receptor 5-HT1F due to its advantage over the tripan class of anti-migraine drugs. Here we report the cryo-EM structure of the 5-HT1F in complex with Lasmiditan and the inhibitory G protein heterotrimer. The structure reveals the mechanism of 5-HT1F-selective activation by Lasmiditan and provides a template for rational design of anti-migraine drugs.

Selective Activation of Inhibitory G-Protein .alpha.-Subunits by Partial Agonists of the Human 5-HT1A Receptor

Biochemistry ◽  
1994 ◽  
Vol 33 (14) ◽  
pp. 4283-4290 ◽  
Author(s):  
Thomas W. Gettys ◽  
Timothy A. Fields ◽  
John R. Raymond
Keyword(s):  
G Protein ◽  
Selective Activation ◽  
Alpha Subunits ◽  
Partial Agonists ◽  
Inhibitory G Protein

scholarly journals Living-Cell Diffracted X-ray Tracking Analysis Confirmed Internal Salt Bridge Is Critical for Ligand-Induced Twisting Motion of Serotonin Receptors

2021 ◽  
Vol 22 (10) ◽  
pp. 5285
Author(s):  
Kazuhiro Mio ◽  
Shoko Fujimura ◽  
Masaki Ishihara ◽  
Masahiro Kuramochi ◽  
Hiroshi Sekiguchi ◽  
...  
Keyword(s):  
Serotonin Receptors ◽  
Serotonin Receptor ◽  
Frame Rate ◽  
Receptor Subtype ◽  
Transmembrane Segment ◽  
Hek 293 ◽  
Gold Nanocrystals ◽  
X Ray ◽  
Time Dynamics ◽  
Analytical Technique

Serotonin receptors play important roles in neuronal excitation, emotion, platelet aggregation, and vasoconstriction. The serotonin receptor subtype 2A (5-HT2AR) is a Gq-coupled GPCR, which activate phospholipase C. Although the structures and functions of 5-HT2ARs have been well studied, little has been known about their real-time dynamics. In this study, we analyzed the intramolecular motion of the 5-HT2AR in living cells using the diffracted X-ray tracking (DXT) technique. The DXT is a very precise single-molecular analytical technique, which tracks diffraction spots from the gold nanocrystals labeled on the protein surface. Trajectory analysis provides insight into protein dynamics. The 5-HT2ARs were transiently expressed in HEK 293 cells, and the gold nanocrystals were attached to the N-terminal introduced FLAG-tag via anti-FLAG antibodies. The motions were recorded with a frame rate of 100 μs per frame. A lifetime filtering technique demonstrated that the unliganded receptors contain high mobility population with clockwise twisting. This rotation was, however, abolished by either a full agonist α-methylserotonin or an inverse agonist ketanserin. Mutation analysis revealed that the “ionic lock” between the DRY motif in the third transmembrane segment and a negatively charged residue of the sixth transmembrane segment is essential for the torsional motion at the N-terminus of the receptor.

scholarly journals Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype

2021 ◽  
Vol 7 (14) ◽  
pp. eabf1268
Author(s):  
Changxiu Qu ◽  
Chunyou Mao ◽  
Peng Xiao ◽  
Qingya Shen ◽  
Ya-Ni Zhong ◽  
...  
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Receptor Activation ◽  
Prostaglandin E ◽  
Toggle Switch ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Ligand Selectivity ◽  
Activation Mechanisms ◽  
Prostaglandin E2 Receptor

Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

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