Davis Dylan E, Ayanlade Jesuferanmi P, Laseinde David T, Subramanian Sandhya, Udell Hannah, Lorimer Donald J, Dranow David M, Edwards Thomas E, Myler Peter J, Asojo Oluwatoyin A
College of Arts and Science, Dartmouth College, Hanover, NH 03755, USA.
Dartmouth Cancer Center, One Medical Center Drive, Lebanon, NH 03756, USA.
Acta Crystallogr F Struct Biol Commun. 2024 Dec 1;80(Pt 12):335-40. doi: 10.1107/S2053230X24011099.
Helicobacter pylori is one of the most common bacterial infections; over two-thirds of the world's population is infected by early childhood. Persistent H. pylori infection results in gastric ulcers and cancers. Due to drug resistance, there is a need to develop alternative treatments to clear H. pylori. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducts structure-function analysis of potential therapeutic targets from H. pylori. Glutamyl-tRNA synthetase (GluRS) is essential for tRNA aminoacylation and is under investigation as a bacterial drug target. The SSGCID produced, crystallized and determined the apo structure of H. pylori GluRS (HpGluRS). HpGluRS has the prototypical bacterial GluRS topology and has similar binding sites and tertiary structures to other bacterial GluRS that are promising drug targets. Residues involved in glutamate binding are well conserved in comparison with Pseudomonas aeruginosa GluRS (PaGluRS), which has been studied to develop promising new inhibitors for P. aeruginosa. These structural similarities can be exploited for drug discovery and repurposing to generate new antibacterials to clear persistent H. pylori infection and reduce gastric ulcers and cancer.
幽门螺杆菌是最常见的细菌感染之一；全球超过三分之二的人口在儿童早期就受到感染。幽门螺杆菌的持续感染会导致胃溃疡和癌症。由于耐药性的存在，需要开发替代疗法来清除幽门螺杆菌。西雅图传染病结构基因组学中心（SSGCID）对幽门螺杆菌潜在的治疗靶点进行结构-功能分析。谷氨酰胺-tRNA合成酶（GluRS）对于tRNA氨基酰化至关重要，目前正在作为一种细菌药物靶点进行研究。SSGCID制备、结晶并确定了幽门螺杆菌GluRS（HpGluRS）的无配体结构。HpGluRS具有典型的细菌GluRS拓扑结构，与其他有前景的细菌药物靶点GluRS具有相似的结合位点和三级结构。与铜绿假单胞菌GluRS（PaGluRS）相比，参与谷氨酸结合的残基高度保守，后者已被研究用于开发有前景的铜绿假单胞菌新抑制剂。这些结构上的相似性可用于药物发现和重新利用，以生成新的抗菌药物，清除幽门螺杆菌的持续感染，减少胃溃疡和癌症。
