Journal of Computer-Aided Molecular Design

, Volume 18, Issue 10, pp 651–664 | Cite as

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

  • Gábor Maksay
  • Miklós Simonyi
  • Zsolt Bikádi


The N-terminal extracellular regions of heterooligomeric 3AB-type human 5-hydroxytryptamine receptors (5-HT 3ABR) were modelled based on the crystal structure of snail acetylcholine binding protein AChBP. Stepwise rotation of subunit A by 5° was performed between -10° and 15° 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° 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–π 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 π–cation–π 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.


docking of agonists homology modelling hydrogen bond analysis 5-hydroxytryptamine3 receptors m-chlorophenylbiguanide subunit rotation 



acetylcholine binding protein


assisted model building with energy refinement


arylquinolinyl piperazine


bicyclooctano-quinolinyl piperazine




γ-aminobutyric acidA


5-hydroxytryptamine (serotonin)


Lamarckian genetic algorithm


protein data bank


relative mean standard deviation

SR 57227

4-amino-(6-chloro-2-pyridyl)-1-piperidine HCl




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Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Molecular Pharmacology Group, Institute for Biomolecular ChemistryChemical Research Centre, Hungarian Academy of SciencesBudapestHungary

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