GPCRs molecular modeling

In the absence of detailed structural information about GPCRs, much of the efforts to interpret experimental results in a structural context has focused on creating molecular representations of these proteins that can incorporate directly and consistently the many types of function-related information (for a recent review, see ref. [5]). In turn, such molecular models serve as hypotheses-generators for experimental probing of functional inferences, and are continuously refined by the data obtained from such experiments. Listed below are some of the main advantages of such an iterative approach, as illustrated in this chapter ... 

Type II Functional mimetics Molecular modeling, HTS GPCR antagonists... 

Fig. 4 A molecular model of the dopamine D2 receptor with a ligand docked in the binding site. The model of the D2 receptor transmembrane helices was constructed from the coordinates of the bacteriorhodopsin structure derived from two-dimensional electron diffraction experiments and is consistent with the projection structure for rhodopsin. The transmembrane helices are represented by a solid ribbon and the drug, apomorphine, is a space filling representation. The top view looking down the helical axis of the receptor clearly delineates the seven transmembrane helices that are the key structural motif for the GPCR superfamily. Some of the helices are inclined relative to the perpendicular to the membrane plane. The bottom view is in the plane of the membrane with the extracellular space at the top of the figure. (Adapted from Ref.t f)...

A molecular model based on the structure of rhodopsin was developed concurrently to mutagenesis studies in order to visualize the environment of the ligand binding site. We have found that the low resolution structure of rhodopsin seiwes as a more versatile template for G protein-coupled receptors (GPCRs) than the coordinates of bacteriorhodopsin [7]. The A2A receptor model was composed in steps including construction and energy minimization of each hehx individually, composition of the helical bundle based on consideration of... 

Structural Biology of GPCRs and Molecular Modeling of Ligand-Receptor Interactions... 

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