7IN5
Crystal structure of A2A in complex with TEP for 3h
Summary for 7IN5
| Entry DOI | 10.2210/pdb7in5/pdb |
| Group deposition | An Integrated Experimental and Computational Pipeline for the Rational Design of GPCR-Targeting Ligands (G_1002334) |
| Descriptor | Adenosine receptor A2a/Soluble cytochrome b562/Adenosine receptor A2a chimera, SODIUM ION, CHOLESTEROL, ... (6 entities in total) |
| Functional Keywords | g-protein-coupled receptor, integral membrane protein, chimera, 2 thermostabilizing mutations, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 57905.62 |
| Authors | |
| Primary citation | 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 Cited by 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: 42129437DOI: 10.1038/s42004-026-02059-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.49 Å) |
Structure validation
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