title: Understanding Corticotropin Releasing Factor Receptor (CRFR) Activation Using Structural Models.
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.
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193, Bellaterra (Barcelona). Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Cordomi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Crete, 71003, Heraklion, Crete. Greece.
authors.forename: George
authors.initials: G
authors.lastname: Liapakis
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadistica, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193, Bellaterra (Barcelona). Spain.
authors.forename: Minos-Timotheos
authors.initials: MT
authors.lastname: Matsoukas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D019204:GTP-Binding Proteins
keywords: Activation; CRF receptors; GPCR structure; corticotropin releasing factor; family B; molecular modeling