Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase
Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase
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确定人 4-羟苯基丙酮酸双加氧酶结合特异性的关键残基的鉴定
DOI：
10.1016/j.ejps.2020.105504
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发表时间：
2020
影响因子：
4.6
通讯作者：
Ying Fu
中科院分区：
文献类型：
--
作者：
Yong-Xuan Liu;Li-Xia Zhao;Tong Ye;Shuang Gao;Jia-Zhong Li;Fei Ye;Ying Fu
4-羟基苯丙酮酸双加氧酶（HPPD，EC 1.13.11.27）是酪氨酸分解代谢途径的第二种酶。其生理功能是催化4-羟基苯基丙酮酸转化为黑黑酸，在哺乳动物和植物中表现出不同的生理作用。通过分子模拟和生物测试的综合应用，提供了三酮抑制剂选择性抑制人HPPD（hHPPD）的见解。通过分子动力学（MD）模拟得到hHPPD与抑制剂的结合自由能，结果与体外抑制实验相符。结合自由能贡献表明hHPPD-抑制剂复合物的形成主要由范德华能量驱动。 Ser226、Asn241、Gln265、Phe336、Phe359 和 Phe364 对所有系统的结合亲和力做出了巨大贡献。在参与nitisinone (NTBC)和hHPPD相互作用的残基中，Tyr221和Leu224突变为Ala导致NTBC结合能力显着降低，是决定抑制剂和hHPPD选择性结合亲和力的两个关键残基。该工作为合理设计针对hHPPD的高选择性抑制剂提供了有价值的理论依据。
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is the second enzyme of the tyrosine catabolic pathway. Its physiological function is to catalyze the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, which displays different physiological effects in mammals and plants. Insights on the selective inhibition of human HPPD (hHPPD) by triketone inhibitors were furnished by the integrated application of molecular simulation and biological testing. The binding free energy ofhHPPD and inhibitors was obtained through molecular dynamics (MD) simulations, and the result was in agreement with the inhibition experimentin vitro. The binding free energy contribution demonstrated that the formation ofhHPPD-inhibitor complexes was mainly driven by van der Waals energy. Ser226, Asn241, Gln265, Phe336, Phe359 and Phe364 made great contributions to binding affinities of all the systems. Among the residues involved in the interaction between nitisinone (NTBC) andhHPPD, Tyr221 and Leu224, whose mutation into Ala caused significant decrease of NTBC binding ability, were two key residues in determining the selective binding affinity of inhibitor andhHPPD. This work provides valuable theoretical basis for rational design of highly selective inhibitors targetinghHPPD.