Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.
Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.
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人色氨酸羟化酶 2 的冷冻电镜结构和激活剂筛选
DOI：
10.3389/fphar.2022.907437
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发表时间：
2022
影响因子：
5.6
通讯作者：
Zhang, Huawei
中科院分区：
文献类型：
--
作者：
Zhu, Kongfu;Liu, Chao;Gao, Yuanzhu;Lu, Jianping;Wang, Daping;Zhang, Huawei
人类色氨酸羟化酶2 （TPH2）是合成血清素的限速酶。它的功能障碍与各种精神疾病有关，如抑郁症、自闭症和双相情感障碍。TPH2在患者体内的稳定性和催化活性通常会降低；因此，筛选能够结合并稳定激活构象TPH2结构的分子是开发精神障碍治疗药物的必要条件。在这里，我们解决了3.0 Å低温电镜结构的TPH2四聚体。然后，根据结构对得到的空腔进行变构位点预测和小分子激活剂筛选。ZINC000068568685被成功选为结合亲和力最高的最佳候选。为了更好地了解配合物的驱动力和结合稳定性，我们进行了分子动力学模拟，结果表明ZINC000068568685具有稳定TPH2四聚体折叠以促进其活性的巨大潜力。该研究可能为开发靶向TPH2治疗心理障碍的新药提供启示。
Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and bipolar disorder. TPH2 is typically decreased in stability and catalytic activity in patients; thus, screening of molecules capable of binding and stabilizing the structure of TPH2 in activated conformation is desired for drug development in mental disorder treatment. Here, we solved the 3.0 Å cryo-EM structure of the TPH2 tetramer. Then, based on the structure, we conducted allosteric site prediction and small-molecule activator screening to the obtained cavity. ZINC000068568685 was successfully selected as the best candidate with highest binding affinity. To better understand the driving forces and binding stability of the complex, we performed molecular dynamics simulation, which indicates that ZINC000068568685 has great potential to stabilize the folding of the TPH2 tetramer to facilitate its activity. The research might shed light on the development of novel drugs targeting TPH2 for the treatment of psychological disorders.
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影响因子：
8.6
作者：
Bikadi Z;Hazai E
通讯作者：
Hazai E
影响因子：
4.7
作者：
Kuhn DM;Sykes CE;Geddes TJ;Jaunarajs KL;Bishop C
通讯作者：
Bishop C
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.1516967113
发表时间：
2016-03-01
影响因子：
11.1
作者：
Arturo, Emilia C.;Gupta, Kushol;Jaffe, Eileen K.
通讯作者：
Jaffe, Eileen K.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH