7W41

Crystal Structure of Human Gastrin Releasing Peptide Receptor in complex with the antagonist PD176252

Summary for 7W41

• Entry DOI: 10.2210/pdb7w41/pdb
• Descriptor: Gastrin-releasing peptide receptor,GlgA glycogen synthase, (2S)-3-(1H-indol-3-yl)-N-[[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl]-2-methyl-2-[(4-nitrophenyl)carbamoylamino]propanamide (2 entities in total)
• Functional Keywords: gpcr, gastrin releasing peptide receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 54959.42

Authors

Peng, S.,Zhan, Y.,Zhang, H. (deposition date: 2021-11-26, release date: 2023-02-22, Last modification date: 2024-10-16)

Primary citation

Peng, S.,Zhan, Y.,Zhang, D.,Ren, L.,Chen, A.,Chen, Z.F.,Zhang, H.
Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy.
Proc.Natl.Acad.Sci.USA, 120:e2216230120-e2216230120, 2023

PubMed 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, β-Ala, Phe, Nle] Bn (6-14), in complex with G heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G 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.

PubMed: 36724251
DOI: 10.1073/pnas.2216230120

Experimental method

X-RAY DIFFRACTION (2.952 Å)