Receptor homology-built models

Database search programs like FASTA [18] or BLAST [19] have been optimised to detect evolutionary relationships between proteins, and are readily adequate for template recognition and (multiple) sequence alignment in cases where the sequence identity is over 25-30% [20], The general procedure is to assume next that the backbone of the model is identical to the one of the template structure and add the side chains onto it [21], although some difficulties may arise with insertions, deletions and local low similarity. 

In some cases, the homology concept can be extended to water molecules buried within the protein matrix [22], and there are already homology-built proteases that include a set of such conserved waters as an important intrinsic feature of the structure [23, 24]. As far as the homology modelling process is concerned, conserved buried waters impose a new type of structural constraints that otherwise would be impossible to define during the structure refinement [23]. 

Once the model is sufficiently refined to satisfy the desired quality criteria, it is just a matter of selecting between the many available computational SBDD tools for studying receptor(model)-ligand interactions. One interesting 

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Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

Metal chelation has also been applied in studies of the structural-functional basis for seven-trans-membrane receptor activation. Using the (i2-adrenergic receptor as a model system, Filing el al. introduced several point mutations to form a metal binding site between trans-membrane helices III, VI and VII and showed that the receptor could be activated by metal ions alone or metal ions chelated by phenanthroline or bipyridine.1391 Based on a homology model built over the rhodopsin receptor crystal structure, helices III, VI and VII would have to move inwards to form a metal chelation site, suggesting that movement of these helices is critical for receptor activation. 

The abundance of experimentally determined protein structures should not, however, obscure the fact that for the majority of protein domains, no structural information is available at all. The coverage of the mammalian proteome by experimentally determined structures is still only about 10-15% and varies between the protein families. Structures of only four G-protein coupled receptors (GPCR), out of about 900, have been determined by crystallography, and only about one-third of the human kinases and the same fraction of the nuclear receptors. For many of those proteins, models by homology can be built (5), although the... 

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