Internet Electronic Journal of Molecular Design
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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
|ABSTRACT - Internet Electron. J. Mol. Des. July 2006, Volume 5, Number 7, 403-415|
Homology Model of the Human 5-HT1A Receptor Using the Crystal
Structure of Bovine Rhodopsin
Urmila J. Joshi, Falgun H. Shah, and Sonali H. Tikhele
Internet Electron. J. Mol. Des. 2006, 5, 403-415
The 5-HT1A receptor, a member of class A GPCRs, is associated with
psychiatric disorders like depression and anxiety, thus representing an
important target for developing new drugs. In the absence of
availability of X-ray crystal structure of the receptor, alternative
approaches must be used for building 3D models of the receptor.
Bacteriorhodopsin was previously used as a template for homology
modeling of GPCRs. However bacteriorhodopsin is not coupled to G
protein and exhibits very low sequence homology with human GPCRs.
The homology model of the human 5-HT1A receptor was constructed
using the published X-ray crystal structure of bovine rhodopsin (PDB
code: 1F88) with MOE 2003.04 (Chemical computing group, Canada).
Due to low overall sequence identity, a segmented approach was used
for model building. The loops, C-terminal and the N-terminal regions
were modeled separately and attached to the transmembrane region.
The model was validated by docking serotonin, an endogenous 5-HT1A
receptor ligand. The model retains global arrangement of GPCRs and
is energetically and geometrically consistent. After docking, the
environment of serotonin in the receptor model is consistent with
reported SAR data for 5-HT1A ligands. This work has provided a first
complete model of the human 5-HT1A receptor for further drug
development. This model can serve as basis for future development of
5-HT1A receptor ligands.