7y3g
Cryo-EM structure of a class A orphan GPCR
Structural highlights
DiseaseGNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] Publication Abstract from PubMedG protein-coupled receptor 12 (GPR12) is an orphan G protein-coupled receptor that is highly expressed in the thalamus of the brain and plays a vital role in driving thalamocortical functions in short-term memory. GPR12 performs high constitutive activity and couples with G(s), increasing the intracellular cyclic adenosine monophosphate (cAMP) level when it is expressed. However, exploitation for drug development is limited since it is unclear how GPR12 initiates self-activation and signal transduction, and whether it can be modulated by endogenous or synthetic ligands. Here, we report the cryo-electron microscopy structure of the GPR12-G(s) complex in the absence of agonists. Our structure reveals the key determinants for the intrinsically high basal activity of GPR12, including extracellular loop 2 partially occupying the orthosteric binding pocket, a tight-packed TM1 and TM7, and unique activation-related residues in TM6 and TM7. Together with mutagenesis data, this study will improve our understanding of the function and self-activation of the orphan receptor GPR12, enable the identification of endogenous ligands, and guide drug discovery efforts that target GPR12. Structural insight into the constitutive activity of human orphan receptor GPR12.,Li H, Zhang J, Yu Y, Luo F, Wu L, Liu J, Chen N, Liu Z, Hua T Sci Bull (Beijing). 2023 Jan 15;68(1):95-104. doi: 10.1016/j.scib.2022.12.023. , Epub 2022 Dec 26. PMID:36593162[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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