Serotonin (5-HT1B) Receptor Bound to Ergotamine

Jourdan Cline '15 and Johanna Klinman '15


I. Introduction

The 5-HT1B receptors inhibit the release of a variety of neurotransmitters, including serotonin. In mammals, these receptors are most commonly found in the central nervous system (CNS) and the cardiovascular system. Also known as 5-hydroxytryptamine (5-HT), serotonin is a critical neuromodulator that has various functions throughout the body. Since serotonin is so key to different parts of the body, as well as to several different systems, there are many well-characterized 5-HT receptors. The 5-HT1, 5-HT2, 5-HT3 and 5-HT4 receptors are all structurally and operationally distinct. Each of these unique receptors bind to the same 5-HT neuromodulator, but they lead to the transduction of different systems.

The 5-HT receptor focused on by Wang et al. (2013) was the 5-HT1B receptor. This receptor is found on the axon terminals of serotonergic and nonserotonergic neurons. In the CNS, it plays a key role in drug reinforcement, stress sensitivity, and other behavioral issues, such as increased anxiety or aggression. Outside of the CNS, activation of this receptor has also been linked to pulmonary vasoconstrictions and other vascular mechanisms.

II. General Structure

The serotonin receptor, 5-HT1B, is composed of extracellular, intracellular, and trans-membrane domains. The is extracellular and acts as a cap to the 7 trans-membrane alpha helices. In the N-terminus , Tyr40 forms a with ligand binding residue Asp352. The interaction of the N-terminus with residue Asp352 may imply that the N-terminus plays a role in ligand recognition. A bond between Cys122 and Cys199 helps stabilize the remaining parts of the extracellular domain that partially cover the orthosteric binding pocket. 

Seven span the trans-membrane domain, four of which combine with the extracellular domain loop to make up the . This is comprised of residues of the orthosteric binding pocket and residues of the extended binding pocket, where small guanine shaped ligands like serotonin (5-HT), ergotamine (ERG), and lysergic acid diethylamine (LSD) bind.

III. ERG Binding

(ERG) is an agonist of the 5-HT1B receptor. It is an anti-migraine drug and has been found to have selective vasoconstrictor properties in the carotid vascular bed of many mammals.

ERG is anchored into the ligand binding pocket by a interaction between Asp129 of the receptor and the charged nitrogen of ERG. Like most monoamine receptors, the 5-HT1B receptor has a fully conserved carboxylate of Asp129. The ligand is further stabilized within the binding pocket by a between the hydrogen of the indole in ERG and Thr134. The side chains of the receptor, Cys133, Ile130, Trp327, Phe330, and PheF331 form a narrow which tightly packs against the planar ergoline ring system. hydrogen bonds in ERG, such as that between the hydrogen of the hydroxyl group and the oxygen of the amide, also help stabilize the molecule while in the binding pocket.

IV. Serotonin Binding

At the current time, it has only been possible to crystalize the serotonin receptor when which has a aromatic ring structure as serotonin.

Unsurprisingly, the 5-HT1B receptor has many of the same interactions with serotonin as it does with ERG. The Asp129 once again forms a with amino side group of serotonin, while Thr134 retains a with the indole N-H hydrogen of serotonin. This hydrogen bond is highly conserved in the binding of serotonin to all receptor sites.
In addition to ERG and serotonin, the serotonin binding site binds several other aromatic molecules. LSD binds to 5-HT receptors and is a potent antagonist at 5-HT7A receptor. Triptans, such as donitriptan and eletriptan, also fit into the promiscuous 5-HT receptor binding site. Norfenfluramine, which is the active metabolic part of the “Fen-Phen” antiobesity cocktail, also binds specifically in the orthosteric binding pocket of the 5HT1B receptor where it forms a with Phe217 and Tyr218.

V. Future Studies

The interactions between ERG and the have thus been well classified. With the continuing improvements made in the field of crystallography every year, crystalizing serotonin in the 5-HT1B receptor will provide more information about the native interaction of serotonin within the body. Further research will look into the interactions between all the 5-HT receptors and the serotonin neuromodulator. Understanding the interactions of serotonin, not only the in 5-HT1B receptor, but also in the 5-HT receptors, will be useful in future medical studies.

VI. References

Clark MS, Neumaier JF. (2001). The 5-HT1B receptor: behavioral implications. Psychopharmacol Bulletin 35(4): 170-85.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP. (1994). International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacological reviews 46(2): 157-203.

Villalón CM, De Vries P, Rabelo G, Centurión D, Sánchez, López A, Saxena P. (1999). Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5-HT1B/1D receptors and 2-adrenoceptors. British journal of pharmacology 126(3): 585-594.

Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou XE, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE. (2013). Structural basis for molecular recognition at serotonin receptors. Science 340(6132): 610-614.

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