title: Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors.
abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR). Crystal structures of a number of Class B GPCR extracellular domains (ECD) bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors.
authors.affiliation: Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Shiva
authors.initials: S
authors.lastname: Kumar
authors.forename: Augen
authors.initials: A
authors.lastname: Pioszak
authors.forename: Chenghai
authors.initials: C
authors.lastname: Zhang
authors.forename: Kunchithapadam
authors.initials: K
authors.lastname: Swaminathan
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C495401:ADCYAP1 protein, human; D006728:Hormones; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D043562:Receptors, G-Protein-Coupled; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D000242:Cyclic AMP