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Review
. 2021 Jan 20;14(2):76.
doi: 10.3390/ph14020076.

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

Qing Wang  1   2 , Yu Zhou  2 , Jianhui Huang  1 , Niu Huang  2   3
Affiliations
Review

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

Qing Wang et al. Pharmaceuticals (Basel). .

Abstract

Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas.

Keywords: 5-HT2BR; GPCR; agonist; antagonist; biased signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Small-molecule ligands in co-crystal structures of 5-HT2BR-ligand complexes.
Figure 2
Figure 2
A comparison of the different small-molecule-bound 5-HT2BR crystal structures. (a) The overall architecture of 5-HT2BR/ERG (cornflower blue, PDB ID: 4IB4), 5-HT2BR/ERG (dark gray, PDB ID: 4NC3), 5-HT2BR/LSD (hot pink, PDB ID: 5TVN), 5-HT2BR/lisuride (light sea green, PDB ID: 6DRX), 5-HT2BR/methylergometrine (salmon, PDB ID: 6DRY), 5-HT2BR/methysergide (purple, PDB ID: 6DRZ), 5-HT2BR/LY266097 (goldenrod, PDB ID: 6DS0) structures aligned through the Cα atoms of residues in helices I to VIII. The 5-HT2BRs are displayed as ribbon cartoons, and the membrane boundaries are displayed as white dots, according to the Orientations of Proteins in Membranes database. (b–d) Specific comparison of residues in (b) PIF, (c) D(E)RY and (d) NPxxY motifs. For clear visualization, residues apart from the motif are hidden, with the exception of the 5-HT2BR/ERG structure (PDB ID: 4IB4). Molecular images were generated using the UCSF Chimera software [115].
Figure 3
Figure 3
A comparison of the 5-HT2BR/ERG (cornflower blue, PDB ID: 4IB4), the 5-HT2BR/ERG-Fab (magenta, PDB ID: 5TUD), the active-state β2AR (orange, PDB ID: 3SN6) and the inactive-state β2AR (forest green, PDB ID: 2RH1) crystal structures. (a) Intracellular view of the overall architecture. The outward movement of helix VI upon activation is indicated by a red arrow. (b) A comparison of structural features in helix VII. The slight inward movement of helix VII and rotation of Y7.53 in the NPxxY motif towards helix VI are highlighted by red arrows. (c,d) A comparison of the residues in (c) PIF and (d) D(E)RY motifs. For clear visualization, residues apart from the motif are hidden, with the exception of the 5-HT2BR/ERG structure (PDB ID: 4IB4). The obvious conformational changes of specific residues upon activation are shown as red arrows. Molecular images were generated using the UCSF Chimera software [115].
Figure 4
Figure 4
Overview of receptor–ligand interactions in the binding pocket. (a) Receptor–ligand interactions in the binding pocket of the 5-HT2BR/LSD structure (PDB ID: 5TVN). Residues of the 5-HT2BR are colored in hot pink, and LSD is colored in cyan. (b) A comparison of the specific interactions in the OBP of ergoline ligand-bound structures: 5-HT2BR/ERG (cornflower blue, PDB ID: 4IB4), 5-HT2BR/LSD (hot pink, PDB ID: 5TVN), 5-HT2BR/lisuride (light sea green, PDB ID: 6DRX), and 5-HT2BR/methylergometrine (salmon, PDB ID: 6DRY). For clear visualization, only the backbone of 5-HT2BR/ERG is shown as a ribbon cartoon. The hydrogen bond interactions are displayed as dashed lines. (c) Comparison of the binding mode of the 5-HT2BR/methylergometrine (salmon, PDB ID: 6DRY) and the A2255.46G mutant 5-HT2BR/methysergide (purple, PDB ID: 6DRZ) structures. (d) Comparison of the specific interactions in the EBP of the 5-HT2BR/LSD (hot pink, PDB ID: 5TVN) and the 5-HT2BR/lisuride structures (light sea green, PDB ID: 6DRX). Hydrogen bond interactions are shown as dashed lines. Molecular images were generated using the UCSF Chimera software [115].
Figure 5
Figure 5
Representative triazine derivatives as selective 5-HT2BR antagonists [65].
Figure 6
Figure 6
Carbonyl guanidine derivatives as dual 5-HT2BR and 5-HT7R antagonists [135,136,137].
Figure 7
Figure 7
Representative chromone derivatives as non-nitrogenous 5-HT2BR antagonists [138,139,140].
Figure 8
Figure 8
Representative C4 phenyl aporphines (27) and tris-(phenylalkyl)amines (28) as 5-HT2BR antagonists [142,143].
Figure 9
Figure 9
Representative biphenyl amide derivative (30) as 5-HT2BR antagonists [144].
Figure 10
Figure 10
Representative chromane derivatives as 5-HT2BR high-affinity ligands [146].
Figure 11
Figure 11
Key pharmacophore features of the 5-HT2BR. Positive electrostatic, hydrogen bond donor and hydrophobic pharmacophore features are colored in blue, green, and cyan, respectively. Pharmacophore features were generated based on the 5-HT2BR crystal structure (PDB ID: 5TVN) using the CavityPlus web server [152]. (a) Association of 5-HT2BR residues and pharmacophore features. Residues close the pharmacophore and contributing to the protein–ligand interactions are shown in hot pink sticks. (b) Association of co-crystal ligands and pharmacophore features. LSD (PDB ID: 5TVN), lisuride (PDB ID: 6DRX), methylergometrine (PDB ID: 6DRY), and LY266097 (PDB ID: 6DS0) are shown as hot pink, light sea green, salmon, and purple stick, respectively. These ligands are aligned based on residues in the binding pocket. Molecular images were generated using the UCSF Chimera software [115].
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