Serotonin Receptor

Serotonin Receptor: 5-HT1B Abstract: 5-hydroxytryptamine 1B (5-HT1B) or serotonin receptor causes the inhibition of specific neurotransmitters like serotonin. The PBD identifier for the crystalline structure of chimeric protein 5-HT1B is 4IAR. The structure of this receptor was obtained through X-ray diffraction with a resolution of 2.7 Å. It is found in humans and Escherichia Coli. The structure’s information is based off of a published journal by Wang, C., Jiang, Y., Ma, J., Wu, H., Wacker, D., Katritch, V., Han, G.W., Liu, W., Huang, X.P., Vardy, E., McCorvy, J.D., Gao, X., Zhou, X.E., Melcher, K., Zhang, C., Bai, F., Yang, H., Yang, L., Jiang, H., Roth, B.L., Cherezov, V., Stevens, R.C., Xu, H.E. (2013) “Structural basis for molecular recognition at serotonin receptors,” Science 340, 610-614. Introduction:     5-hydroxytryptamine 1B (5-HT1B) receptors, 5-HT receptors, or serotonin receptor is essential for wide range of physiological processes in the human body, including sleep-wake cycles, mood, memory, appetite, perception, and many other functions. 5-HT receptors are commonly in the Central and Peripheral Nervous System, that can be grouped into seven subfamilies (5-HT1-7). In that, except 5-HT3R subfamily, which is a ligand-gated ion channel, 5-HT1B and all other receptors are heterotrimeric guanine nucleotide binding G protein coupled receptors (GPCRs). 5-HT1B’s main job is to both excite or inhibit the neurotransmitter serotonin; hence, its name serotonin receptor. In general, 5-HT1B is composed of seven-transmembrane alpha helical, intracellular loop, and extracellular loop domains. Also, its pocket domain, which is composed of orthosteric and extended binding pocket, is important for binding of ligands like serotonin, ergotamine (ERG), and Lysergic acid diethylamide (LSD). The crystal model of 5-HT1B-BRIL in complex with agonist ergotamine is usually used to reveal the structure and function of 5-HT1B receptor. Structure and Functions: 5-hydroxytryptamine 1B (5-HT1B) receptors is one kind of GPCRs that interact with serotonin released in nerve cells. Serotonin bind to the outside portion the 5-HT1B’s receptor, induces the change in receptor’s shape, and lead to the excitatory response in the cells. Many different drugs, like Ergotamine, has similar structure with serotonin and bound to the site where serotonin is normally occupied. As show in figure 1, the cluster of grey bubbles inside the receptor is Ergotamine. Since 5-HT1B is a transmembrane protein, it is composed of mostly hydrophobic residues (magenta) to suit with the nonpolar environment of the inside membrane (Figure 1). 0-508000Figure 1: The overall structure of 5-HT1B. 5-HT1B is mostly composed of alpha helical bundles, that serve as both receptor and membrane protein. Two grey spacefill proteins are ergotamine and (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate ligands. Yellow shows hydrophilic side and magenta shows hydrophobic side of the receptor. Overall, 5-HT1B is composed of transmembrane alpha helical, intracellular, extracellular domains. In figure 2, seven alpha helical bundles (red), that extent the transmembrane domain, is oriented to make up the ligand binding pocket inside. The pocket domain is comprised of orthosteric binding pocket (yellow) and extended binding pocket (blue), where ligands like serotonin, ERG (white), and lysergic acid dimethylamine (LSH) bind to. -1568458004300 Figure 2: The ligand binding site of 5-HT1B, or pocket domain, is comprised of the extended binding pocket (blue) and the orthosteric binding pocket (yellow). It also shows the seven alpha helical bundle of transmembrane domain (red) outside and ergotamine ligands (white) inside the pocket. At the extracellular domain of 5-HT1B receptor, the N-terminal is act as a small cover to the transmembrane domain. In that, the Tyr 40 (green) on N-terminal form the hydrogen bond (red) with Asp 352 (yellow) that play a role in ligand recognition, figure3. Another disulfide bond (white), between Cys 122 (blue) and Cys 199 (blue), is formed to stabilize the deeper parts of the orthosteric binding pocket (figure 3). Figure 4 displays the closer look of how ERG anchored inside the binding pocket. The ERG shown here is divided into two part, the upper gray part (with red and blue) and lower pink part. The pink part is planar ergoline ring of ERG is packed closely against ligand binding pocket (green), also called hydrophobic cleft. In addition, the salt bridge is formed between ASP 129 of the receptor and the nitrogen of ERG and the hydrogen bond between indole N-H of ERG and Thr 134 of receptor further increase the affinity of the binding. 1564102085500 Figure 3: The closer view of 5-HT1B ‘s extracellular loop domain of the ligand binding site. On the N-terminal (green), residue Tyr 40 (also green) form a hydrogen bond (red) with residue Asp 352 (yellow). Also, a disulfide bond bond (white) between Cys 122 (blue) and Cys 199 (blue). 800102984500Figure 4: The illustration of the close-view of how ergotamine (ERG) ligand is anchored into the binding pocket. In that, the sulfide bond between Asp 129 with charged nitrogen of ERG and hydrogen bond between Thr 134 help to stabilize the inside of binding pocket. The pink part of the ligand demonstrates the planar ergoline ring system of ERG; green part demonstrates the hydrophobic left of ligand binding pocket. Not show in the figure, the intracellular hydrogen bonds within the binding pocket, such that between the hydroxyl group of receptor and oxygen of amide of ERG, also help stabilize the local structure. Most of the 5-HT receptors are distinguish from each other by the difference in size and component of residues inside of its binding site. Biomedical/Health Relevance: Currently, there is ongoing studies on the usage of 5-HT1B receptors in antidepressant drugs. This receptor is responsible for the response of serotonin released into the brain and throughout the body. Many of these drugs target serotonin because of the hypothesis that depression causes a decrease of serotonin levels in the brain. With the growing rate of people with Major Depression Disorders (MDD), more antidepressants are being prescribe but only half of patients are responding to selective serotonin reuptake inhibitors. SSRI allows the serotonin to remain temporary in the brain instead of being reabsorbed. Clinical, in vivo, and postmortem studies are being conducted to determine the reasoning to why some people respond to the drug while others don’t. Also, these receptors are being studied in mediation such as ergotamine (ERG) and dihydroergotamine (DHE) that prevents or reduces migraines. This signals to the brain for pain is inhibited due to this receptor. References Tiger, Mikael et al. “The 5-HT1B receptor - a potential target for antidepressant treatment.” Psychopharmacology vol. 235,5 (2018): 1317-1334. C. Wang, Y. Jiang, J. Ma, H. Wu, D. Wacker, V. Katritch, G. W. Han, W. Liu, X. P. Huang, E. Vardy, J. D. McCorvy, X. Gao, X. E. Zhou, K. Melcher, C. Zhang, F. Bai, H. Yang, L. Yang, H. Jiang, B. L. Roth, V. Cherezov, R. C. Stevens & H. E. Xu (2013) Structural basis for molecular recognition at serotonin receptors. Science 340, 610-619. Wang, C., Jiang, Y., Ma, J., Wu, H., Wacker, D., Katritch, V., Han, G.W., Liu, W., Huang, X.P., Vardy, E., McCorvy, J.D., Gao, X., Zhou, X.E., Melcher, K., Zhang, C., Bai, F., Yang, H., Yang, L., Jiang, H., Roth, B.L., Cherezov, V., Stevens, R.C., Xu, H.E. (2013) “Structural basis for molecular recognition at serotonin receptors,” Science 340, 610-614. M. Berger, J. A. Gray & B. L. Roth (2009) The expanded biology of serotonin. Annual Review of Medicine 60, 355-366. Authentication -10348068900