Nature communications · 2026
Covalent allosteric inhibition of AARS1 lactyltransferase.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Huang Yunyuan, Liu Siying, Tian Luyang, Tang Yang, Dou Yilin, Wang Huiling, Zheng Tao, Wang Mingyang, Li Runhao, Wang Zhi, Zhou Zhaocai, Chen Xin, Min Jinrong
Аннотация
Alanyl-tRNA synthetase 1 (AARS1) was recently identified as a lactyltransferase responsible for protein lactylation, a modification associated with epigenetic regulation and metabolic adaptation. Here, we report compound XY353, which covalently binds C184 of AARS1, inducing steric clashes with F175 and triggering structural rearrangements in the region that displace W176, a key residue for lactate binding. By means of a combination of a variety of biophysical and enzymatic assays with MD simulations and structural analysis, we show that XY353 and its derivative XY353-1 inhibit AARS1 by competing with lactate via the C184-F175-W176 relay, supporting a covalent allosteric mechanism of inhibition, which is further confirmed by our cellular data that XY353-1 reduces lactylation of the AARS1 substrate YAP and suppresses the proliferation of HGC-27 cells. Collectively, these findings identify a covalent allosteric mechanism for AARS1 inhibition and provide chemical tools to explore its biological functions.