Abstract

The corticotropin-releasing factor type 1 and 2 receptors (CRF1R and CRF2R) belong to the secretin-like family, also known as class B1, of G protein-coupled receptors (GPCRs). Several endogenous hormones mediate their responses through the CRF receptors, such as CRF and the urocortins. The structures for the N-terminus extracellular domain of both CRF1R and CRF2R in complex with peptidic ligands were released a few years ago and permitted the study of hormone binding to the orthosteric binding site. Until the crystal structure of the transmembrane domain of human CRF1R in its inactive state bound to an allosteric antagonist became available. Together with the crystal structures of the transmembrane domain of the glucagon receptor (GCGR), they have enabled the structural alignment between the rhodopsin and secretin-like families, which permits the direct comparison of the functional domains in both classes. In this report, we review the current structural landscape, in addition to the knowledge regarding activation of both CRF receptors and the generalization to secretin-like GPCRs in general. Thus, significant effort was put in trying to identify possible analogous microswitches in the class B1, with the hypothesis that both families could maintain a similar arrangement of their functional domain.

Keywords: Activation, corticotropin releasing factor, family B, GPCR structure, molecular modeling, CRF receptors.

Graphical Abstract