Receptor structure and modelling

With some doubt over the validity of bacteriorhodopsin as a suitable template for GPCRs, a number of models have been constructed without the use of a template. Thus, Dahl et al constructed a model of the dopamine D2 receptor. From the available sequences, hydropathy plots confirmed the presence of seven hydrophobic 

The Unger/Baldwin model became the new template on which many new models were based . However, Unger et al published a 3-dimensional electron density map of frog rhodopsin at 7.5 A resolution, shown in figure 4. This map provides a wealth of data to assist in the modelling of these receptors. Baldwin et reanalysed the 493 class A GPCR sequences available in 1997 in the same manner as 

The most recent projection map of bovine rhodopsin is to 5 A resolution. Two-dimensional crystals were obtained of bovine rhodopsin that showed p22 2 symmetry. From this, electron diffraction patterns could be taken which gave an improved projection map, shown in figure 6. 

There are several observable differences between the 1995 and 1997 projection structures. Firstly, the curve of electron density towards helix 5 is longer in the 1997 map, with a more defined peak of density in this region. Therefore, there is more density between helices 3 and 5 than predicted in previous projection maps. Secondly, the tilt (to the vertical) on helix 5 has been underestimated. Earlier projection maps identified helix 5 as a clear peak, suggesting that helix 5 should be untilted. However, the 1997 projection map indicates an elongated peak for helix 5, which suggests that helix 5 has a well-defined tilt. Finally, electron density is now detected between helices 6 and 2 and between helices 6 and 7. The density between helices 6 and 7 may indicate that helix 7 is perturbed towards the extracellular side. This perturbation in helix 7 was predicted from modelling studies as early as 1986. 

It is clear that there is no one correct receptor model. However, since the early modelling work based on bacteriorhodopsin, receptor models have become increasingly more accurate regarding their ability to explain experimental observations. Further improvements in the resolution of electron density maps will only add to the accuracy of these models, allowing them to become a predictive tool also. 

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