Impact of helix irregularities on sequence alignment and homology modeling of G protein-coupled receptors.

Comparison of the crystal structures of G protein-coupled receptors (GPCRs) revealed backbone irregularities in the majority of the transmembrane (TM) helices. Among these, wide (π bulge) and tight (3(10)) helical turns on TM2 and TM5 deserve special attention because of their proximity to the ligand binding site. These irregularities are related to residue insertion or deletion (reflected by inclusion of gaps in sequence alignments) accumulated during the evolution of these two helices. These findings have direct implications for the sequence alignments, phylogeny reconstruction, and homology modeling of class A GPCRs.