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Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1.
Structure ( IF 4.4 ) Pub Date : 2018-11-08 , DOI: 10.1016/j.str.2018.10.002
Ian Mitchelle S de Vera 1 , Paola Munoz-Tello 1 , Jie Zheng 2 , Venkatasubramanian Dharmarajan 2 , David P Marciano 3 , Edna Matta-Camacho 1 , Pankaj Kumar Giri 1 , Jinsai Shang 1 , Travis S Hughes 1 , Mark Rance 4 , Patrick R Griffin 5 , Douglas J Kojetin 5
Structure ( IF 4.4 ) Pub Date : 2018-11-08 , DOI: 10.1016/j.str.2018.10.002
Ian Mitchelle S de Vera 1 , Paola Munoz-Tello 1 , Jie Zheng 2 , Venkatasubramanian Dharmarajan 2 , David P Marciano 3 , Edna Matta-Camacho 1 , Pankaj Kumar Giri 1 , Jinsai Shang 1 , Travis S Hughes 1 , Mark Rance 4 , Patrick R Griffin 5 , Douglas J Kojetin 5
Affiliation
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Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.
中文翻译：
在孤儿核受体Nurr1中定义规范配体结合口袋。
核受体相关的1蛋白（Nurr1 / NR4A2）是一种孤儿核受体（NR），被认为可以在没有规范的配体结合袋（LBP）的情况下发挥作用。Nurr1配体结合结构域（LBD）的晶体结构显示，在该区域中没有其他具有溶剂可及的载脂蛋白LBP的NR与合成和天然配体结合的物理空间。使用溶液核磁共振波谱，氢/氘交换质谱和分子动力学模拟，我们证明了推定的经典Nurr1 LBP是动态的，具有较高的溶剂可及性，在微秒到毫秒的时间范围内两个或多个构象之间的交换，以及可以从塌陷的结晶构象扩展以允许不饱和脂肪酸的结合。
更新日期：2019-02-26
中文翻译：
在孤儿核受体Nurr1中定义规范配体结合口袋。
核受体相关的1蛋白（Nurr1 / NR4A2）是一种孤儿核受体（NR），被认为可以在没有规范的配体结合袋（LBP）的情况下发挥作用。Nurr1配体结合结构域（LBD）的晶体结构显示，在该区域中没有其他具有溶剂可及的载脂蛋白LBP的NR与合成和天然配体结合的物理空间。使用溶液核磁共振波谱，氢/氘交换质谱和分子动力学模拟，我们证明了推定的经典Nurr1 LBP是动态的，具有较高的溶剂可及性，在微秒到毫秒的时间范围内两个或多个构象之间的交换，以及可以从塌陷的结晶构象扩展以允许不饱和脂肪酸的结合。
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