6lpb
From Proteopedia
Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein
Structural highlights
Function[GBG2_BOVIN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [PACA_HUMAN] Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells.[1] [GBB1_RAT] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [PACR_HUMAN] This is a receptor for PACAP-27 and PACAP-38. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. May regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, prolactin, epinephrine, and catecholamine. May play a role in spermatogenesis and sperm motility. Causes smooth muscle relaxation and secretion in the gastrointestinal tract. Publication Abstract from PubMedPituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide hormone. The PACAP receptor PAC1R, which belongs to the class B G-protein-coupled receptors (GPCRs), is a drug target for mental disorders and dry eye syndrome. Here, we present a cryo-EM structure of human PAC1R bound to PACAP and an engineered Gs heterotrimer. The structure revealed that transmembrane helix TM1 plays an essential role in PACAP recognition. The extracellular domain (ECD) of PAC1R tilts by ~40 degrees compared with that of the glucagon-like peptide-1 receptor (GLP-1R) and thus does not cover the peptide ligand. A functional analysis demonstrated that the PAC1R ECD functions as an affinity trap and is not required for receptor activation, whereas the GLP-1R ECD plays an indispensable role in receptor activation, illuminating the functional diversity of the ECDs in class B GPCRs. Our structural information will facilitate the design and improvement of better PAC1R agonists for clinical applications. Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein.,Kobayashi K, Shihoya W, Nishizawa T, Kadji FMN, Aoki J, Inoue A, Nureki O Nat Struct Mol Biol. 2020 Mar;27(3):274-280. doi: 10.1038/s41594-020-0386-8. Epub, 2020 Mar 9. PMID:32157248[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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