Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy

Abstract

Gastrin 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 , β-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.

A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides

“…Peptide amidation not only improves peptide stability but also influences molecular recognition at neuropeptide receptors . For example, replacement of the C-terminal amides in substance P, bombesin, peptide YY, cholecystokinin, and oxytocin with a carboxylic acid severely reduces receptor binding. − This is consistent with the C-terminus of most amidated neuropeptides occupying space deep within the ligand-binding site, which has been implied for some time by biophysical studies and observed more recently in several ligand-bound receptor structures. − Fortunately, unsubstituted amides can be readily generated from nitrobenzyl-derived caging groups that are stable in biological buffers. − Thus, C-terminal amide caging is attractive as a potentially general caging strategy that could provide access to photoactivatable variants of more than half of known neuropeptides.…”

Structure-function analysis of plant G-protein regulatory mechanisms identifies key Gα-RGS protein interactions

“…SmGPA and OsRGA1 share similar bi-domain structures observed in other eukaryote Gα proteins ( 8 , 9 , 10 , 13 ). A three-dimensional structure similarity search using the DALI server identifies multiple Gα proteins, including AtGPA1 ( 13 ), human and murine Gα13 ( 31 , 32 ), human Gs ( 33 ), Entamoeba histolytica Gα ( 34 ), human Gq ( 35 ), and human Gi ( 36 ), that share 30 to 56% amino acid identity with both SmGPA and OsRGA1, as well as the conservation of three-dimensional fold with 1.6 to 2.8 Å r.m.sd for 225 to 372 C α -atoms in these enzymes from varied organisms. The Ras-like GTPase domain of SmGPA with the GTP analog consists of five α-helices (α1, α9-12) surrounding a six-stranded β-sheet (β1a-b1f) with the helical domain (α2-α7) connected by two linking segments ( Fig.…”

Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer

“…Gastrin-releasing peptide receptor (GRPR), a member of the bombesin G-protein-coupled receptor family is overexpressed in various malignant tumors across anatomical sites such as the breast, prostate, lung, and gastrointestinal tract [ 17 ]. GRPR plays roles in human physiological mechanisms, including regulating gastrointestinal motility, gastric emptying, and smooth muscle contractions.…”