8W1V

The beta2 adrenergic receptor bound to a bitopic ligand

これはPDB形式変換不可エントリーです。

8W1V の概要

• エントリーDOI: 10.2210/pdb8w1v/pdb
• 分子名称: Beta-2 adrenergic receptor,Endolysin, Nanobody60, (2S)-1-[(3-{1-[4-(4-{(2S)-2-hydroxy-3-[(propan-2-yl)amino]propoxy}phenyl)butyl]-1H-1,2,3-triazol-4-yl}propyl)amino]-3-(2-propylphenoxy)propan-2-ol, ... (4 entities in total)
• 機能のキーワード: signal transduction, bitopic ligand, , signaling protein, gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 153648.52

構造登録者

Gaiser, B.,Danielsen, M.,Xu, X.,Jorgensen, K.,Fronik, P.,Marcher-Rorsted, E.,Wrobe, T.,Hirata, K.,Liu, X.,Mathiesen, J.,Pedersen, D. (登録日: 2024-02-19, 公開日: 2024-07-17, 最終更新日: 2024-11-13)

主引用文献

Gaiser, B.I.,Danielsen, M.,Xu, X.,Ropke Jorgensen, K.,Fronik, P.,Marcher-Rorsted, E.,Wrobel, T.M.,Liu, X.,Mosolff Mathiesen, J.,Sejer Pedersen, D.
Bitopic Ligands Support the Presence of a Metastable Binding Site at the beta 2 Adrenergic Receptor.
J.Med.Chem., 67:11053-11068, 2024

PubMed Abstract: Metastable binding sites (MBS) have been observed in a multitude of molecular dynamics simulations and can be considered low affinity allosteric binding sites (ABS) that function as stepping stones as the ligand moves toward the orthosteric binding site (OBS). Herein, we show that MBS can be utilized as ABS in ligand design, resulting in ligands with improved binding kinetics. Four homobivalent bitopic ligands (-) were designed by molecular docking of ()-alprenolol (()-ALP) in the cocrystal structure of the β adrenergic receptor (βAR) bound to the antagonist ALP. Ligand displayed a potency and affinity similar to ()-ALP, but with a >4-fold increase in residence time. The proposed binding mode was confirmed by X-ray crystallography of ligand in complex with the βAR. This ligand design principle can find applications beyond the βAR and G protein-coupled receptors (GPCRs) as a general approach for improving the pharmacological profile of orthosteric ligands by targeting the OBS and an MBS simultaneously.

PubMed: 38952152
DOI: 10.1021/acs.jmedchem.4c00578

実験手法

X-RAY DIFFRACTION (3 Å)