6ZDV

Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with Chromone 5d

6ZDV の概要

• エントリーDOI: 10.2210/pdb6zdv/pdb
• 関連するPDBエントリー: 6ZRD
• 分子名称: Adenosine receptor A2a,Soluble cytochrome b562,Adenosine receptor A2a, [2-methyl-3-(4-methyl-1,3-thiazol-2-yl)-4-oxidanylidene-6-propyl-chromen-7-yl] ethanoate, SODIUM ION, ... (8 entities in total)
• 機能のキーワード: g protein-coupled receptor, membrane protein, receptor, protein binding
• 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: 54204.65

構造登録者

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. (登録日: 2020-06-15, 公開日: 2020-09-16, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.13 Å)