Structural and Functional Insights into CRF Peptides and Their Receptors

Simple Summary Corticotropin-releasing factor or hormone (CRF or CRH) belongs to the family of CRF peptide and non-peptide analogs (or CRF ligands), which play important roles in many physiologic and pathophysiologic conditions. Several of the CRF ligands have shown considerable therapeutic potential in the treatment of various diseases. The CRF ligands act by interacting with two types of receptors. This work describes the structure of CRF ligands and their receptors, as well as the mode of CRF ligand binding to receptors and the activation mechanism of the latter. Understanding the structural basis of CRF ligand binding and activation of their receptors opens avenues for the development of novel drugs targeting CRF receptors.Abstract Corticotropin-releasing factor or hormone (CRF or CRH) and the urocortins regulate a plethora of physiological functions and are involved in many pathophysiological processes. CRF and urocortins belong to the family of CRF peptides (CRF family), which includes sauvagine, urotensin, and many synthetic peptide and non-peptide CRF analogs. Several of the CRF analogs have shown considerable therapeutic potential in the treatment of various diseases. The CRF peptide family act by interacting with two types of plasma membrane proteins, type 1 (CRF1R) and type 2 (CRF2R), which belong to subfamily B1 of the family B G-protein-coupled receptors (GPCRs). This work describes the structure of CRF peptides and their receptors and the activation mechanism of the latter, which is compared with that of other GPCRs. It also discusses recent structural information that rationalizes the selective binding of various ligands to the two CRF receptor types and the activation of receptors by different agonists.