7w41 | pdb_00007w41
Crystal Structure of Human Gastrin Releasing Peptide Receptor in complex with the antagonist PD176252
Structural highlights
FunctionQ9V2J8_PYRAB GRPR_HUMAN Receptor for gastrin-releasing peptide (GRP) (PubMed:1655761). Signals via association with G proteins that activate a phosphatidylinositol-calcium second messenger system, resulting in Akt phosphorylation. Contributes to the regulation of food intake. Contributes to the perception of prurient stimuli and transmission of itch signals in the spinal cord that promote scratching behavior, but does not play a role in the perception of pain. Contributes primarily to nonhistaminergic itch sensation. In one study, shown to act in the amygdala as part of an inhibitory network which inhibits memory specifically related to learned fear (By similarity). In another study, shown to contribute to disinhibition of glutamatergic cells in the auditory cortex via signaling on vasoactive intestinal peptide-expressing cells which leads to enhanced auditory fear memories (By similarity). Contributes to the induction of sighing through signaling in the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity (By similarity).[UniProtKB:P21729][1] Publication Abstract from PubMedGastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe(6), beta-Ala(11), Phe(13), Nle(14)] Bn (6-14), in complex with G(q) heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G(q) proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus. Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy.,Peng S, Zhan Y, Zhang D, Ren L, Chen A, Chen ZF, Zhang H Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2216230120. doi: , 10.1073/pnas.2216230120. Epub 2023 Feb 1. PMID:36724251[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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