6ZDR

Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with Chromone 4d

Summary for 6ZDR

• Entry DOI: 10.2210/pdb6zdr/pdb
• Descriptor: Adenosine receptor A2a,Soluble cytochrome b562,Adenosine receptor A2a, [3-(4-methyl-1,3-thiazol-2-yl)-4-oxidanylidene-6-propyl-chromen-7-yl] ethanoate, SODIUM ION, ... (7 entities in total)
• Functional Keywords: g protein-coupled receptor, membrane protein, receptor, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 54056.33

Authors

Verdon, G.,Jespers, W.,Azuaje, J.,Majellaro, M.,Keranen, H.,Garcia-mera, X.,Congreve, M.,Deflorian, F.,de Graaf, C.,Zhukov, A.,Dore, A.,Mason, J.,Aqvist, J.,Cooke, R.,Sotelo, E.,Gutierrez-de-Teran, H. (deposition date: 2020-06-15, release date: 2020-09-16, Last modification date: 2024-11-06)

Primary citation

Jespers, W.,Verdon, G.,Azuaje, J.,Majellaro, M.,Keranen, H.,Garcia-Mera, X.,Congreve, M.,Deflorian, F.,de Graaf, C.,Zhukov, A.,Dore, A.S.,Mason, J.S.,Aqvist, J.,Cooke, R.M.,Sotelo, E.,Gutierrez-de-Teran, H.
X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A 2A Adenosine Receptor Antagonists.
Angew.Chem.Int.Ed.Engl., 59:16536-16543, 2020

PubMed Abstract: We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A adenosine receptor (AR). Eight A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A AR, an emerging target in immuno-oncology.

PubMed: 32542862
DOI: 10.1002/anie.202003788

Experimental method

X-RAY DIFFRACTION (1.918 Å)