The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays.
Most of the currently available G protein-coupled receptor (GPCR) crystal structures represent an inactive receptor state, which has been considered to be suitable only for the discovery of antagonists and inverse agonists in structure-based computational ligand screening. Using the β(2)-adrenergic receptor (B2AR) as a model system, we show that a dynamic homology model based on an "active" opsin structure without further incorporation of experimental data performs better than the crystal structure of the inactive B2AR in finding agonists over antagonists/inverse agonists. Such "active-like state" dynamic homology models can therefore be used to selectively identify GPCR agonists in in silico ligand libraries.
Department of Biophysics, University of Bochum, Bochum, Germany.
Michael
M
Schneider
Steffen
S
Wolf
Jürgen
J
Schlitter
Klaus
K
Gerwert
D001665:Binding Sites; D008024:Ligands; D056004:Molecular Dynamics Simulation; D055355:Opsins / Q000737:chemistry*; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*
D008024:Ligands; D055355:Opsins; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled