G protein-coupled receptors (GPCRs) interact with an extraordinary diversity of ligands by means of their extracellular domains and/or the extracellular part of the transmembrane (TM) segments. Each receptor subfamily has developed specific sequence motifs to adjust the structural characteristics of its cognate ligands to a common set of conformational rearrangements of the TM segments near the G protein binding domains during the activation process. Thus, GPCRs have fulfilled this adaptation during their evolution by customizing a preserved 7TM scaffold through conformational plasticity. We use this term to describe the structural differences near the binding site crevices among different receptor subfamilies, responsible for the selective recognition of diverse ligands among different receptor subfamilies. By comparing the sequence of rhodopsin at specific key regions of the TM bundle with the sequences of other GPCRs we have found that the extracellular region of TMs 2 and 3 provides a remarkable example of conformational plasticity within Class A GPCRs. Thus, rhodopsin-based molecular models need to include the plasticity of the binding sites among GPCR families, since the "quality" of these homology models is intimately linked with the success in the processes of rational drug-design or virtual screening of chemical databases. © 2007 Bentham Science Publishers Ltd.
|Journal||Current Topics in Medicinal Chemistry|
|Publication status||Published - 1 May 2007|
- Conformational plasticity
- Helix-helix interaction
- Hydrogen bond network
- Transmembrane helices