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Research Themes Drug discovery

Membrane Proteome: GPCR Substrate Recognition and Functional Selectivity

SBKB [doi:10.1038/sbkb.2012.153]
Featured Article - August 2013
Short description: Crystal structures of 5-HT receptors bound to antimigraine drugs offer insights into ligand specificity and signaling bias.

Differences in the expanded ligand binding pocket of 5-HT1B (light blue) and 5-HT2B (green) result in conformational differences in the bound ERG (cyan and magenta, respectively). Figure courtesy of Daniel Wacker.

The neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) signals through the 5-HT receptors, a family of G protein-coupled receptors (GPCRs). In addition to signaling via canonical G protein pathways, GPCRs can signal via noncanonical pathways, frequently mediated via β-arrestin. These receptors are the targets for many drugs, including antimigraine medications, antipsychotics and antidepressants, but the use of many of these drugs is complicated by side effects caused by off-target interactions with 5-HT receptor subtypes and related biogenic amine receptors. Some drugs are also able to elicit biased signaling, preferentially activating canonical or noncanonical pathways (as opposed to activating both pathways equally).

To gain a better understanding of how serotonergic drugs are recognized by 5-HT receptors, Xu, Roth, Stevens and colleagues (PSI GPCR Network) determined the structures of the antimigraine drug ergotamine (ERG) bound to its primary target, the 5-HT1B receptor (PDB 4IAR), and to the 5-HT2B receptor (PDB 4IB4). They also obtained the structure of 5-HT1B in complex with dihydroergotamine (PDB 4IAQ).

The receptors are comprised of seven transmembrane (7TM) α-helices. The ligand-binding cavity in each receptor, formed by residues in helices III, V, VI and VII, is capped by the second extracellular loop (ECL2). The ergoline ring of ERG sits deep within the 7TM core in 5-HT1B and 5-HT2B, forming similar key interactions in a conserved orthosteric binding pocket in both receptors. 5-HT1B has a much broader extended binding pocket than that of 5-HT2B, due to sequence differences and an outward shift at the extracellular end of helix V. As a result, the phenyl group of the ERG cyclic tripeptide makes different interactions with and adopts distinct conformations within each of the receptors. Mutational and docking analyses reveal that interactions with the ergoline moiety of ERG and related compounds appear to be the driving force for binding. Indeed, these results explain how the hallucinogen lysergic acid diethylamide (LSD), another ergoline, can interact promiscuously with 5-HT receptors. In contrast, triptans, antimigraine drugs that are 5-HT analogs, interact weakly with 5-HT2B because their specific shapes do not fit in the receptor's relatively small extended binding pocket.

The authors also show that LSD, ERG and other ergolines display biased signaling for β-arrestin at 5-HT2B, but are essentially unbiased at 5-HT1B. Examination of the ERG-bound crystal structures reveals that the P-I-F motif — Pro, Ile, and Phe residues found at the base of the ligand binding pocket— is in an active-like conformation in the 5-HT1B structure, but in an intermediate active one in the 5-HT2B structure. Investigation of the structural rearrangements induced on the cytoplasmic side of the receptors indicates that the 5-HT1B structure has features of an agonist-induced, activated receptor, with a shift in helix VI associated with G protein-coupled signaling. On the other hand, the 5-HT2B structure shows conformational changes in helix VII associated with β-arrestin signaling and only minor changes to helix VI, characteristics of both active and inactive states.

These findings provide a framework for understanding ligand specificity within GPCR subtypes and uncover the structural basis for signaling bias, and shall contribute to the rational development of drugs for this important receptor family.

Michelle Montoya


  1. C. Wang et al. Structural basis for molecular recognition at serotonin receptors.
    Science. 340, 610-614 (2013). doi:10.1126/science.1232807

  2. D. Wacker et al. Structural features for functional selectivity at serotonin receptors.
    Science. 340, 615-619 (2013). doi:10.1126/science.1232808

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