Beyond Class A Modeling Of Other Gpcr Families

A multitude of clinically relevant GPCRs can be found outside of the Class A GPCR family. The calcitonin, glucagon, and parathyroid hormone receptors in the secretin (Class B) family and calcium-sensing, metabotropic glutamate, and GABA binding receptors in the glutamate (Class C) family are validated drug discovery targets [122] . Several additional GPCRs in these families are considered putative therapeutic targets, including several recently deorpha-nized receptors implicated in cancer and other pathologies [123]. Unlike Class A (rhodopsin like) receptors, the majority of Classes B and C receptors bind their endogenous ligands at the N-terminal extracellular domain. However, additional allosteric sites have been identified within the TM domains of these receptors that at least partially overlap with the retinal binding cavity in the rhodopsin [124]. Allosteric modulators may exhibit improved drug selectivity, as these allosteric sites are expected to be more structurally diverse than the N-terminal orthosteric ligand binding pocket [125, 126] . Additionally, overall structural similarity in the TM domains of all GPCRs may facilitate the application of rational design approaches developed for Class A receptors to other GPCR families and orphan GPCRs.

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