An overview of recent developments in GPCR modelling: methods and validation

Abstract

The superfamily of G-protein-coupled receptors (GPCRs) are single polypeptide chains possessing seven hydrophobic transmembrane-spanning segments that couple with an effector molecule through a trimeric G protein complex. A knowledge of their three-dimensional structure could be of great help in the task of understanding their function and in the rational design of specific ligands. However, as GPCRs are membrane-bound proteins, high-resolution structural characterisation is still an extremely difficult task. For this reason, great importance has been placed on molecular modelling studies, and in the last few years especially on homology modelling (HM) techniques. The HM procedure starts from the recently resolved crystal structure of the bovine rhodopsin, but other experimental data such as site-directed mutagenesis and substituted-cysteine accessibility method studies are extremely necessary. In this review the most common HM computational steps are reported and discussed together with the most recent alternative approaches and main validation methods. Future possible targets of the HM are presented and expected improvements in computational methods are considered.