7INX

Crystal structure of A2A in complex with FU2-57

これはPDB形式変換不可エントリーです。

7INX の概要

• エントリーDOI: 10.2210/pdb7inx/pdb
• Group deposition: An Integrated Experimental and Computational Pipeline for Crystallographic Fragment Screening in Lipid Cubic Phase Targeting the A2A Receptor (G_1002334)
• 分子名称: Adenosine receptor A2a/Soluble cytochrome b562/Adenosine receptor A2a chimera,Soluble cytochrome b562,Adenosine receptor A2a, SODIUM ION, THEOPHYLLINE, ... (8 entities in total)
• 機能のキーワード: g-protein-coupled receptor, integral membrane protein, chimera, 2 thermostabilizing mutations, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58336.00

構造登録者

Huang, C.-Y.,Cheng, R.Y.K.,Metz, A. (登録日: 2025-08-21, 公開日: 2026-05-20)

主引用文献

Huang, C.Y.,Cheng, R.,Metz, A.,Bucher, D.,Andres, F.,Bacchin, A.,Glover, H.,Sager, C.P.,Wang, M.,Steinmetz, M.O.,Hennig, M.,Sharpe, M.
An integrated experimental and computational pipeline for crystallographic fragment screening of membrane protein in the lipid cubic phase.
Commun Chem, 2026

PubMed Abstract: X-ray crystallographic fragment screening is a powerful strategy in modern drug discovery, enabling the identification of small-molecule starting points for rational hit-to-lead optimization. While highly effective for soluble proteins, its application to membrane proteins remains challenging due to low expression yields, high hydrophobicity, and the complexities of crystallization-particularly when using lipid cubic phase (LCP), which is often essential for high-resolution structural studies of targets like G-protein-coupled receptors (GPCRs). In this study, we present a methodology that integrates high-throughput X-ray crystallography with computational modeling and complementary biophysical validation to overcome these barriers. Using a thermostabilized human adenosine A receptor crystallized in LCP as a test system, we screened 568 fragments and identified 23 initial hits. The work represents the first large-scale fragment screening effort targeting crystals of a membrane protein grown in LCP. Structure-guided virtual screening of these hits led to the design of 109 follow-up compounds, of which 56 yielded crystal structures. Of these, 19 were additionally confirmed to bind by grating-coupled interferometry (GCI), providing complementary biophysical validation. Our results demonstrated the feasibility and effectiveness of this integrated approach for fragment-based drug discovery on membrane proteins crystallized in LCP. Moreover, the detection of ligands at a previously uncharacterized intracellular pocket in a GPCR highlights the potential of this strategy to accelerate the discovery of therapeutically relevant compounds for challenging drug targets.

PubMed: 42129437
DOI: 10.1038/s42004-026-02059-7

実験手法

X-RAY DIFFRACTION (2.31 Å)