8SAI

Cryo-EM structure of GPR34-Gi complex

8SAI の概要

• エントリーDOI: 10.2210/pdb8sai/pdb
• EMDBエントリー: 40270
• 分子名称: Probable G-protein coupled receptor 34, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (6 entities in total)
• 機能のキーワード: complex, agonist, membrane protein, lipid binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 169895.03

構造登録者

Yong, X.H.,Zhao, C.,Yan, W.,Shao, Z.H. (登録日: 2023-04-01, 公開日: 2023-10-04, 最終更新日: 2024-11-13)

主引用文献

Xia, A.,Yong, X.,Zhang, C.,Lin, G.,Jia, G.,Zhao, C.,Wang, X.,Hao, Y.,Wang, Y.,Zhou, P.,Yang, X.,Deng, Y.,Wu, C.,Chen, Y.,Zhu, J.,Tang, X.,Liu, J.,Zhang, S.,Zhang, J.,Xu, Z.,Hu, Q.,Zhao, J.,Yue, Y.,Yan, W.,Su, Z.,Wei, Y.,Zhou, R.,Dong, H.,Shao, Z.,Yang, S.
Cryo-EM structures of human GPR34 enable the identification of selective antagonists.
Proc.Natl.Acad.Sci.USA, 120:e2308435120-e2308435120, 2023

PubMed Abstract: GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and G protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.

PubMed: 37733739
DOI: 10.1073/pnas.2308435120

実験手法

ELECTRON MICROSCOPY (3.27 Å)