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-Structure paper
タイトル | Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 120, Issue 6, Page e2216230120, Year 2023 |
掲載日 | 2023年2月7日 |
著者 | Shuman Peng / Yuting Zhan / Dongqi Zhang / Lu Ren / Anqi Chen / Zhou-Feng Chen / Haitao Zhang / |
PubMed 要旨 | 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, ...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. |
リンク | Proc Natl Acad Sci U S A / PubMed:36724251 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.952 - 3.0 Å |
構造データ | EMDB-32297, PDB-7w3z: EMDB-32298, PDB-7w40: PDB-7w41: |
化合物 | ChemComp-8B8: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPCR / Gastrin Releasing Peptide Receptor |