Abstract
Using sets of experimental distance restraints, which characterize active or inactive receptor conformations, and the X-ray crystal structure of the inactive form of bovine rhodopsin as a starting point, we have constructed models of both the active and inactive forms of rhodopsin and the β 2-adrenergic G-protein coupled receptors (GPCRs). The distance restraints were obtained from published data for site-directed crosslinking, engineered zinc binding, site-directed spin-labeling, IR spectroscopy, and cysteine accessibility studies conducted on class A GPCRs. Molecular dynamics simulations in the presence of either "active" or "inactive" restraints were used to generate two distinguishable receptor models. The process for generating the inactive and active models was validated by the hit rates, yields, and enrichment factors determined for the selection of antagonists in the inactive model and for the selection of agonists in the active model from a set of nonadrenergic GPCR drug-like ligands in a virtual screen using ligand docking software. The simulation results provide new insights into the relationships observed between selected biochemical data, the crystal structure of rhodopsin, and the structural rearrangements that occur during activation.
Original language | English |
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Pages (from-to) | 67-84 |
Number of pages | 18 |
Journal | Proteins: Structure, Function and Genetics |
Volume | 56 |
Issue number | 1 |
Early online date | 16 Apr 2004 |
DOIs | |
Publication status | Published - 1 Jul 2004 |
Externally published | Yes |
Keywords
- Active conformation
- Adrenergic
- Agonist
- Antagonist
- Docking
- G-protein coupled receptor
- Inactive conformation
- Molecular modeling
- Rhodopsin
ASJC Scopus subject areas
- Structural Biology
- Biochemistry
- Molecular Biology