Journal article
Spatial orientation of the antagonist granisetron in the ligand-binding site of the 5-HT3 receptor
Molecular pharmacology, v 68(2), pp 365-371
Aug 2005
PMID: 15914697
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The serotonin type 3 receptor (5-HT(3)R) is a member of the cys-loop ligand-gated ion channel (LGIC) superfamily. Like almost all membrane proteins, high-resolution structural data are unavailable for this class of receptors. We have taken advantage of the high degree of homology between LGICs and the acetylcholine binding protein (AChBP) from the freshwater snail Lymnea stagnalis, for which high-resolution structural data are available, to create a structural model for the extracellular (i.e., ligand-binding) domain of the 5-HT(3)R and to perform a series of ligand docking experiments to delineate the architecture of the ligand-binding site. Structural models were created using homology modeling with the AChBP as a template. Docking of the antagonist granisetron was carried out using a Lamarckian genetic algorithm to produce models of ligand-receptor complexes. Two energetically similar conformations of granisetron in the binding site were obtained from the docking simulations. In one model, the indazole ring of granisetron is near Trp90 and the tropane ring is near Arg92; in the other, the orientation is reversed. We used double-mutant cycle analysis to determine which of the two orientations is consistent with experimental data and found that the data are consistent with the model in which the indazole ring of granisetron interacts with Arg92 and the tropane ring interacts with Trp90. The combination of molecular modeling with double-mutant cycle analysis offers a powerful approach for the delineation of the architecture of the ligand-binding site.
Metrics
Details
- Title
- Spatial orientation of the antagonist granisetron in the ligand-binding site of the 5-HT3 receptor
- Creators
- Dong Yan - Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102, USAMichael M White
- Publication Details
- Molecular pharmacology, v 68(2), pp 365-371
- Publisher
- American Society for Pharmacology and Experimental Therapeutics (ASPET); United States
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000230549900013
- Scopus ID
- 2-s2.0-23044435706
- Other Identifier
- 991014878414104721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Pharmacology & Pharmacy