MSITE: A new computational tool for comparison of homological proteins in holo form

The mechanism by which nuclear receptors respond differentially to structurally distinct agonists is not a well understood process. However, it is now obvious that transcriptional activity of nuclear receptors is a function of their interactions with co-activators. Recently, we released a new computational tool, CCOMP, for comparing side chain conformations in crystal structures of homologous protein complexes. Application of the CCOMP program revealed that 20-epi-1α,25-(OH)2D3 changes the side chain conformation of vitamin D receptor amino acids residing mostly far away from the ligand-receptor contacts. This strongly suggests that the ligand-co-activator signaling pathway involves indirect interactions between amino acids lining the binding pocket and outer surface residues that could attract co-activators. To facilitate identification of amino acids transmitting the subtle receptor changes upon ligand/modulator binding we developed another simple tool, MSITE. The program automatically lists the nearest neighbors of a given amino acid (for example neighbors of residues that are in contact with a ligand or reorient their side chains in the presence of a co-factor) in an arbitrary number of compared complexes. Comparison of seven binary vitamin D receptor complexes holding as ligands the analogs of 1α,25-(OH)2D3 with inverted configuration at carbon 14 or 20, or with incorporated oxolane ring bridging carbons 20 and 23, is reported.