Homology Models of Rhodopsin-Like GPCRS

1 Multiple sequence alignment structural motifs as anchor points 

These residues are conserved in the rhodopsin-like family and form a hydrogen bond network, directly or mediated by water molecules, as revealed by the crystal structure of rhodopsin [25]. This interaction has also been confirmed by site-directed mutagenesis experiments showing that D2.50 and N7.49 have a coordinated substitution pattern in a number of GPGRs, so that when D2.50 changes to N2.50, N7.49 changes to D7.49 [11,26-28]. These three residues contribute to the stabilization of the three dimensional structure of TMl, TM2 and TM7 and their mutation produces serious effects in the function of the receptor. This is the case for the /32 adrenoreceptor [11], TRHR [26], NK2, [27,28], and CBl [29] among others. N7.49 is also part of the well know NPXXY motif that will be discussed in detail later. 

The central arginine (R3.50) of the D/ERY motif makes a double hydrogen bond with the adjacent D3.49 and a highly conserved glutamic acid in TM6, E6.30. Eor a number of GPGRs, non-conservative mutations in this motif induce a constitutive 

After a careful alignment of the conserved structural motifs, there are other criteria that should be applied to obtain a meaningful alignment [14]. Briefly, these criteria can be summarized as (i) exclusion of insertions or deletions in the transmembrane domains and relocation of these gaps to the loops (preferably close to non-conserved glycine or proline), (ii) proper identification of the limits of the transmembrane domains through the analysis of the periodicity of conservation 

In many other cases, there is no significant homology between the loops of the GPCR we are modeling and the loops in rhodopsin. In those cases ab initio methods should be used to predict the most likely conformations of the loops some of those methods will be discussed below. 

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