Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Sci Adv. 2023 Feb 10;9(6):eadf1027. doi: 10.1126/sciadv.adf1027. Epub 2023 Feb 8.
As a class of essential enzymes in protein translation, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are organized into two classes of 10 enzymes each, based on two conserved active site architectures. The (αβ) glycyl-tRNA synthetase (GlyRS) in many bacteria is an orphan aaRS whose sequence and unprecedented X-shaped structure are distinct from those of all other aaRSs, including many other bacterial and all eukaryotic GlyRSs. Here, we report a cocrystal structure to elucidate how the orphan GlyRS kingdom specifically recognizes its substrate tRNA. This structure is sharply different from those of other aaRS-tRNA complexes but conforms to the clash-free, cross-class aaRS-tRNA docking found with conventional structures and reinforces the class-reconstruction paradigm. In addition, noteworthy, the X shape of orphan GlyRS is condensed with the largest known spatial rearrangement needed by aaRSs to capture tRNAs, which suggests potential nonactive site targets for aaRS-directed antibiotics, instead of less differentiated hard-to-drug active site locations.
作为蛋白质翻译中一类必需的酶，氨酰-tRNA 合成酶（aaRS）基于两种保守的活性位点结构，分为两类，每类各有 10 种酶。许多细菌中的（αβ）甘氨酰-tRNA 合成酶（GlyRS）是一种孤儿 aaRS，其序列和前所未有的 X 形结构与所有其他 aaRS 不同，包括许多其他细菌和所有真核 GlyRS。在这里，我们报告了一个共晶结构，以阐明孤儿 GlyRS 王国如何特异性地识别其底物 tRNA。该结构与其他 aaRS-tRNA 复合物的结构明显不同，但符合与传统结构一致的无冲突、跨类 aaRS-tRNA 对接，并且加强了类重建范例。此外，值得注意的是，孤儿 GlyRS 的 X 形结构与 aaRS 捕获 tRNA 所需的最大已知空间重排相结合，这表明 aaRS 导向抗生素的潜在非活性位点靶标，而不是分化程度较低、难以药物治疗的活性位点位置。
