Privileged Structures in GPCRs

Abstract

Certain kinds of ligand substructures recur frequently in pharmacologically successful synthetic compounds. For this reason they are called privileged structures. In seeking an explanation for this phenomenon, it is observed that the privileged structure represents a generic substructure that matches commonly recurring conserved structural motifs in the target proteins, which may otherwise be quite diverse in sequence and function. Using sequence-handling tools, it is possible to identify which other receptors may respond to the ligand, as dictated on the one hand by the nature of the privileged substructure itself or by the rest of the ligand in which a more specific message resides. It is suggested that privileged structures interact with the partially exposed receptor machinery responsible for the switch between the active and inactive states. Depending on how they have been designed to interact, one can predispose these substructures to favour either one state or the other; thus privileged structures can be used to create either agonists or antagonists. In terms of the mechanism of recognition, the region that the privileged structures bind to are rich in aromatic residues, which explains the prevalence of aromatic groups and atoms such as sulphur or halogens in many of the ligands. Finally, the approach described here can be used to design drugs for orphan receptors whose function has not yet been established experimentally.

Systematic residue numbering convention: GPCRs are of varying sizes, anywhere between approximately 315 and approximately 620 residues in length. This clearly poses problems for the creation of a standard numbering scheme for comparing residue positions across families. However, the length of the TM segments is more or less constant, and each TM has a pattern of conserved residues. Various schemes have been devised to pivot the numbering system about the most conserved residue in each TM. The GPCRDB system is just one of these. In this work, the residue numbers will take the form: (TM number)_(Position in that TM from the N-terminal end). Conversion to other standard numbering conventions can be made by consulting Bywater (2005) or Bondensgaard et al. (2004).

Orientation convention: Unlike molecules of water-soluble proteins, which are oriented either in the frame of the user's 3D graphics device or with the orientation that they had in the crystal lattice, membrane proteins should be considered in relation to their orientation relative to the membrane, usually this is horizontal (in the , plane). In the convention employed here, the cytosolic side of the membrane is placed below the membrane bilayer and the extracellular side above. Directional prepositions used in the text, “up” and “down”, “deeper down” etc. (i.e. along the z axis), are defined according to this convention.