pKa Calculations of GPCRs: Understanding Protonation States in Receptor Activation,Journal of Chemical Information and Modeling

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pKa Calculations of GPCRs: Understanding Protonation States in Receptor Activation
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-16 , DOI: 10.1021/acs.jcim.4c01125
Carlos A V Barreto _{1,

2} , João N M Vitorino ₃ , Pedro B P S Reis ₃ , Miguel Machuqueiro ₃ , Irina S Moreira _{2,

4}

Affiliation

The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation–conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp^2.50 residue in five different class A GPCRs (active and inactive conformations) using a linear response approximation (LRA) pK_a calculation protocol. We observed consistent differences (1.3 pK units) for the macroscopic pK_a values between the inactive and active states of the A2AR and B2AR receptors, indicating the protonation of Asp^2.50 during GPCR activation. This process seems to be specific and not conserved, as no differences were observed in the pK_a values of the remaining receptors (CB1R, NT1R, and GHSR).

中文翻译：

GPCR 的 pKa 计算：了解受体激活中的质子化状态

可用 G 蛋白偶联受体 (GPCR) 结构的增加对于帮助理解其激活过程至关重要。然而，质子化-构象耦合在 GPCR 激活中的作用仍需阐明。我们使用线性响应近似 (LRA) p K _a计算协议研究了高度保守的 Asp ^2.50残基在五种不同的 A 类 GPCR（活性和非活性构象）中的质子化行为。我们观察到 A2AR 和 B2AR 受体的非活性和活性状态之间的宏观pKa_值存在一致的差异（1.3 p K单位），表明 GPCR 激活期间 Asp ^2.50的质子化。这个过程似乎是特定的且不保守，因为在其余受体（CB1R、NT1R 和 GHSR）的 p K _a值中没有观察到差异。

更新日期：2024-08-16

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