Asp 残基在人 Nudix 水解酶 MTH1 中的质子化状态有助于其广泛的底物识别。
Protonation states of Asp residues in the human Nudix hydrolase MTH1 contribute to its broad substrate recognition.
机构信息
Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
Priority Organization for Innovation and Excellence, Kumamoto University, Japan.
出版信息
FEBS Lett. 2023 Jul;597(13):1770-1778. doi: 10.1002/1873-3468.14611. Epub 2023 Mar 23.
Human MutT homolog 1 (MTH1), also known as Nudix-type motif 1 (NUDT1), hydrolyzes 8-oxo-dGTP and 2-oxo-dATP with broad substrate recognition and has attracted attention in anticancer therapeutics. Previous studies on MTH1 have proposed that the exchange of the protonation state between Asp119 and Asp120 is essential for the broad substrate recognition of MTH1. To understand the relationship between protonation states and substrate binding, we determined the crystal structures of MTH1 at pH 7.7-9.7. With increasing pH, MTH1 gradually loses its substrate-binding ability, indicating that Asp119 is deprotonated at pH 8.0-9.1 in 8-oxo-dGTP recognition and Asp120 is deprotonated at pH 8.6-9.7 in 2-oxo-dATP recognition. These results confirm that MTH1 recognizes 8-oxo-dGTP and 2-oxo-dATP by exchanging the protonation state between Asp119 and Asp120 with higher pK .
人类 MutT 同源物 1（MTH1），也称为 Nudix 基序 1（NUDT1），可水解 8-氧代-dGTP 和 2-氧代-dATP，具有广泛的底物识别能力，因此在抗癌治疗中受到关注。先前对 MTH1 的研究表明，Asp119 和 Asp120 之间质子化状态的交换对于 MTH1 的广泛底物识别至关重要。为了了解质子化状态与底物结合之间的关系，我们测定了 pH 值为 7.7-9.7 的 MTH1 晶体结构。随着 pH 值的增加，MTH1 逐渐失去其底物结合能力，这表明在 8-氧代-dGTP 识别中 Asp119 在 pH8.0-9.1 时去质子化，在 2-氧代-dATP 识别中 Asp120 在 pH8.6-9.7 时去质子化。这些结果证实，MTH1 通过 Asp119 和 Asp120 之间质子化状态的交换来识别 8-氧代-dGTP 和 2-氧代-dATP，其 pK 更高。
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