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Allosteric interactions in the parathyroid hormone GPCR-arrestin complex formation.
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2020-07-06 , DOI: 10.1038/s41589-020-0567-0
Lisa J Clark 1, 2 , James Krieger 3 , Alex D White 1, 4 , Vasyl Bondarenko 5 , Saifei Lei 1 , Fei Fang 1 , Ji Young Lee 3 , Pemra Doruker 3 , Thore Böttke 6 , Frederic Jean-Alphonse 1 , Pei Tang 1, 3, 5 , Thomas J Gardella 7 , Kunhong Xiao 1 , Ieva Sutkeviciute 1 , Irene Coin 6 , Ivet Bahar 3 , Jean-Pierre Vilardaga 1
Affiliation  

Peptide ligands of class B G-protein-coupled receptors act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor–arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that initial binding of the PTH C-terminal part constrains the conformation of the flexible PTH N-terminal signaling epitope before a second binding event occurs. A ‘hot-spot’ PTH residue, His9, that inserts into the PTHR transmembrane domain at this second step allosterically engages receptor–arrestin coupling. A conformational change in PTHR intracellular loop 3 permits favorable interactions with β-arrestin’s finger loop. These results unveil structural determinants for PTHR–arrestin complex formation and reveal that the two-step binding mechanism proceeds via cooperative fluctuations between ligand and receptor, which extend to other class B G-protein-coupled receptors.



中文翻译:

甲状旁腺激素 GPCR-arrestin 复合物形成中的变构相互作用。

B 类 G 蛋白偶联受体的肽配体通过两步结合过程起作用,但将它们的细胞外结合与细胞内受体-抑制蛋白相互作用联系起来的基本机制尚不完全清楚。使用核磁共振、交联耦合质谱、信号实验和甲状旁腺激素 (PTH) 1 型受体 (PTHR) 的计算方法,我们表明 PTH C 端部分的初始结合限制了灵活的 PTH N 端的构象在第二次结合事件发生之前的信号表位。在第二步插入 PTHR 跨膜结构域的“热点”PTH 残基 His9 变构地参与受体-抑制蛋白偶联。PTHR 细胞内环 3 的构象变化允许与 β-arrestin 的指环进行有利的相互作用。

更新日期:2020-07-06
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