9M42

Structure-based discovery of potent agonists of the orphan receptor GPR139

これはPDB形式変換不可エントリーです。

9M42 の概要

• エントリーDOI: 10.2210/pdb9m42/pdb
• EMDBエントリー: 63614
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: gpr139, complex, g protein, structural 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: 157432.95

構造登録者

Cabezadevaca, I.,Trapkov, B.,Shen, L.,Pezeshki, M.,Zhang, X.H.,Liu, Z.j.,Hauser, A.S.,Carlsson, J. (登録日: 2025-03-03, 公開日: 2026-01-21)

主引用文献

Cabeza de Vaca, I.,Trapkov, B.,Shen, L.,Vo, D.D.,Zhang, X.,Yang, Y.,Pezeshki, M.,Zhang, X.,Ballgren, F.,Saleh, A.,Tarnovskiy, A.V.,Radchenko, D.S.,Moroz, Y.S.,Brauner-Osborne, H.,Svenningsson, P.,Kihlberg, J.,Liu, Z.J.,Hauser, A.S.,Carlsson, J.
Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139.
Nat Commun, 17:129-129, 2025

PubMed Abstract: The orphan G protein-coupled receptor (GPCR) GPR139 attracts interest as a target for neuropsychiatric disorders. Whereas the physiological functions of GPR139 remain elusive, a high-resolution receptor structure is now available. To assess whether structural information enables ligand discovery, we computationally dock 235 million compounds to the GPR139 binding site. Of 68 top-ranked compounds evaluated experimentally, five are full agonists with potencies ranging from 160 nM to 3.6 µM. Structure-guided optimization identifies one of the most potent GPR139 agonists, and a cryo-EM structure of the receptor-ligand complex confirms the predicted binding mode. Functional characterization provides insights into GPR139 signalling, and one agonist elicits behavioural effects in mice. We also explore the potential to replace experimental structure determination with the deep-learning method AlphaFold3, revealing a limited capability of artificial intelligence to model receptor-ligand interactions for understudied GPCRs. The results demonstrate how high-resolution GPCR structures combined with large-library docking can accelerate drug discovery.

PubMed: 41365886
DOI: 10.1038/s41467-025-66845-y

実験手法

ELECTRON MICROSCOPY (3.2 Å)