title: Structure of class B GPCR corticotropin-releasing factor receptor 1.
abstract: Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.
authors.affiliation: Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Hollenstein
authors.forename: James
authors.initials: J
authors.lastname: Kean
authors.forename: Andrea
authors.initials: A
authors.lastname: Bortolato
authors.forename: Robert K Y
authors.initials: RK
authors.lastname: Cheng
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Doré
authors.forename: Ali
authors.initials: A
authors.lastname: Jazayeri
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cooke
authors.forename: Malcolm
authors.initials: M
authors.lastname: Weir
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Marshall
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000145:classification* / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000145:classification; D000099052:CRF Receptor, Type 1
chemical_list: C529296:(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; D000631:Aminopyridines; D008024:Ligands; D018019:Receptors, Corticotropin-Releasing Hormone; D050637:Receptors, Dopamine D3; D000099052:CRF Receptor, Type 1