7ini | pdb_00007ini

Crystal structure of A2A in complex with F135

spinqualitylabelsall models 7ini, resolution 2.57Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ini is a 1 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.57Å Ligands: A1COV, CLR, NA, OLA, OLC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AA2AR_HUMAN Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMed 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(2A) 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. An integrated experimental and computational pipeline for crystallographic fragment screening of membrane protein in the lipid cubic phase.,Huang CY, Cheng R, Metz A, Bucher D, Andres F, Bacchin A, Glover H, Sager CP, Wang M, Steinmetz MO, Hennig M, Sharpe M Commun Chem. 2026 May 13. doi: 10.1038/s42004-026-02059-7. PMID:42129437 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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