title: Structure of Class B GPCRs: new horizons for drug discovery.
abstract: Class B GPCRs of the secretin family are important drug targets in many human diseases including diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. X-ray crystal structures for the glucagon receptor and corticotropin-releasing factor receptor 1 have now been published. In this review, we analyse the new structures and how they compare with each other and with Class A and F receptors. We also consider the differences in druggability and possible similarity in the activation mechanisms. Finally, we discuss the potential for the design of small-molecule modulators for these important targets in drug discovery. This new structural insight allows, for the first time, structure-based drug design methods to be applied to Class B GPCRs.
authors.affiliation: Heptares Therapeutics Limited, Welwyn Garden City, Hertfordshire, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bortolato
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Doré
authors.forename: Kaspar
authors.initials: K
authors.lastname: Hollenstein
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Tehan
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mason
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018027:Receptors, Glucagon / Q000737:chemistry; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C029937:secretin receptor; D000099052:CRF Receptor, Type 1
keywords: CRF1 receptor; Class B; GPCR; GPCR molecular signature; HHM; druggability; glucagon receptor; smoothened receptor