Subunit rotation models activation of serotonin 5-HT3AB receptors by agonists

Abstract

The N-terminal extracellular regions of heterooligomeric 3AB-type human 5-hydroxytryptamine receptors (5-HT3ABR) were modelled based on the crystal structure of snail acetylcholine binding protein AChBP. Stepwise rotation of subunit A by 5 degrees was performed between -10 degrees and 15 degrees to mimic agonist binding and receptor activation. Anticlockwise rotation reduced the size of the binding cavity in interface AB and reorganised the network of hydrogen bonds along the interface. AB subunit dimers with different rotations were applied for docking of ligands with different efficacies: 5-HT, m-chlorophenylbiguanide, SR 57227, quinolinyl piperazine and lerisetron derivatives. All ligands were docked into the dimer with -10 degrees rotation representing ligand-free, open binding cavities similarly, without pharmacological discrimination. Their ammonium ions were in hydrogen bonding distance to the backbone carbonyl of W183. Anticlockwise rotation and contraction of the binding cavity led to distinctive docking interactions of agonists with E129 and cation-pi interactions of their ammonium ions. Side chains of several further amino acids participating in docking (Y143, Y153, Y234 and E236) are in agreement with the effects of point mutations in the binding loops. Our model postulates that 5-HT binds to W183 in a hydrophobic cleft as well as to E236 in a hydrophilic vestibule. Then it elicits anticlockwise rotation to draw in loop C via pi-cation-pi interactions of its ammonium ion with W183 and Y234. Finally, closure of the binding cavity might end in rebinding of 5-HT to E129 in the hydrophilic vestibule.

Interactions of Granisetron with an Agonist-Free 5-HT3A Receptor Model

“…The following residues are predicted to be involved in intersubunit interactions (within 4 Å distance of residues): R55−Y141, K81−Q211, Q83−Q211, D132−Q157, W183−P155, L184−Y143, and L184−K154. Additionally, the predicted intersubunit hydrogen-bonding network of the ligand-bound ionophore predicted to form via W183, Y234, Y143, and Y153 ( , ) is not present in the ligand-free model. The significantly different local structures of the “lid-open” and “lid-shut” binding cavities suggest that modeling based on the nACh receptor enables us to model binding interactions of antagonists more correctly.…”

“…Modeling studies have utilized this structural information from the snail AChBP in the analysis of receptor−ligand interactions. Homology modeling of the 5-HT 3 receptor based on this structure has provided information about the molecular basis of ligand−receptor interactions ( − ). The effects of individual residues on ligand binding have been tested by site-directed mutagenesis ( − ).…”

Specific Targeting of Peripheral Serotonin 5-HT3Receptors. Synthesis, Biological Investigation, and Structure−Activity Relationships

“…In order to define the pharmacophoric features of our new series of arylpiperazine ligands, we performed a 3D structure−activity relationship (SAR) analysis taking into account previously reported pharmacophoric and receptor models for 5-HT 3 R ,− (Table 1 of Supporting Information (SI) and Figure 1 of SI). For this goal, compounds 4a − o (Table ) were subjected to computational studies in order to analyze their conformational and electronic behavior.…”

MD‐354: What is It Good For?

“…For a series of MD‐354–related phenylguanidines, affinities varied in the same manner as in their cognate PBGs (Dukat et al 2001), suggesting a similar mode of binding, and further implying that aryl substituents play a major role in modulating receptor affinity. 5‐HT 3 receptor homology models have been constructed to examine the docking of 5‐HT (Reeves et al 2003), m CPBG (Maksay et al 2004), and other 5‐HT 3 receptor agonists. Although the binding of MD‐354 in such models has not yet been reported, it is likely that this compound will bind in a manner similar to that of m CPBG.…”