Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion.
Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion.
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酪氨酸靶向的共价抑制锌离子辅助的tRNA合成酶。
DOI：
10.1038/s42003-023-04517-7
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发表时间：
2023-01-27
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
氨酰-tRNA合成酶（AARSs）是一种重要的蛋白质合成酶家族，是药物开发的重要靶点。虽然已经鉴定了几种不同类型的阿尔斯抑制剂，但尚未报道阿尔斯共价抑制剂。在这里，我们提出了五个不寻常的晶体结构表明，苏氨酰-tRNA合成酶（ThrRS）是共价抑制的天然产物，obbenorin（OB）。与OB形成共价键的残基是ThrRS活性中心中的酪氨酸，其通常不被共价抑制剂修饰。OB的邻苯二酚部分上的两个羟基与ThrRS活性中心中的保守锌离子形成两个配位键。因此，OB的β-内酯结构可以与相邻酪氨酸的酚基发生酯交换反应，在化合物与酶之间形成共价键，并允许其硝基苯结构占据tRNA的结合位点。此外，当酪氨酸被赖氨酸或甚至弱亲核性精氨酸取代时，也可以形成类似的键。我们对一类以多个氨基酸残基为靶点的阿尔斯共价抑制剂的作用机制的报道，将有助于癌症和感染性疾病药物的发现。E.大肠杆菌苏氨酰-tRNA合成酶与天然产物obacriorin（OB）复合物的研究表明，OB是一种独特的共价抑制剂。
Aminoacyl-tRNA synthetases (AARSs), a family of essential protein synthesis enzymes, are attractive targets for drug development. Although several different types of AARS inhibitors have been identified, AARS covalent inhibitors have not been reported. Here we present five unusual crystal structures showing that threonyl-tRNA synthetase (ThrRS) is covalently inhibited by a natural product, obafluorin (OB). The residue forming a covalent bond with OB is a tyrosine in ThrRS active center, which is not commonly modified by covalent inhibitors. The two hydroxyl groups on the o-diphenol moiety of OB form two coordination bonds with the conserved zinc ion in the active center of ThrRS. Therefore, the β-lactone structure of OB can undergo ester exchange reaction with the phenolic group of the adjacent tyrosine to form a covalent bond between the compound and the enzyme, and allow its nitrobenzene structure to occupy the binding site of tRNA. In addition, when this tyrosine was replaced by a lysine or even a weakly nucleophilic arginine, similar bonds could also be formed. Our report of the mechanism of a class of AARS covalent inhibitor targeting multiple amino acid residues could facilitate approaches to drug discovery for cancer and infectious diseases. Structures of E. coli threonyl-tRNA synthetase in complex with natural product obafluorin (OB) reveal that OB is a unique covalent inhibitor.
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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
DOI：
10.1007/bf00343181
发表时间：
1970-01-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
NASS, G;HASENBANK, R
通讯作者：
HASENBANK, R
影响因子：
120.1
作者：
Boike, Lydia;Henning, Nathaniel J.;Nomura, Daniel K.
通讯作者：
Nomura, Daniel K.
白藜芦醇 A 对 I 类合成酶 tRNA 结合位点的抑制机制
影响因子：
16.6
作者：
Chen B;Luo S;Zhang S;Ju Y;Gu Q;Xu J;Yang XL;Zhou H
通讯作者：
Zhou H
影响因子：
16.6
作者：
Fang, Pengfei;Yu, Xue;Jeong, Seung Jae;Mirando, Adam;Chen, Kaige;Chen, Xin;Kim, Sunghoon;Francklyn, Christopher S.;Guo, Min
通讯作者：
Guo, Min