8WIJ

Crystal structure of E. coli ThrS catalytic domain mutant L489M in complex with Obafluorin

8WIJ の概要

• エントリーDOI: 10.2210/pdb8wij/pdb
• 分子名称: Threonine--tRNA ligase, N-(2,3-dihydroxybenzoyl)-4-(4-nitrophenyl)-L-threonine, ZINC ION, ... (4 entities in total)
• 機能のキーワード: threonine--trna ligase, ligase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 96774.56

構造登録者

Qiao, H.,Wang, Z.,Wang, J.,Fang, P. (登録日: 2023-09-24, 公開日: 2024-07-24)

主引用文献

Qiao, H.,Wang, Z.,Yang, H.,Xia, M.,Yang, G.,Bai, F.,Wang, J.,Fang, P.
Specific glycine-dependent enzyme motion determines the potency of conformation selective inhibitors of threonyl-tRNA synthetase.
Commun Biol, 7:867-867, 2024

PubMed Abstract: The function of proteins depends on their correct structure and proper dynamics. Understanding the dynamics of target proteins facilitates drug design and development. However, dynamic information is often hidden in the spatial structure of proteins. It is important but difficult to identify the specific residues that play a decisive role in protein dynamics. Here, we report that a critical glycine residue (Gly463) dominates the motion of threonyl-tRNA synthetase (ThrRS) and the sensitivity of the enzyme to antibiotics. Obafluorin (OB), a natural antibiotic, is a novel covalent inhibitor of ThrRS. The binding of OB induces a large conformational change in ThrRS. Through five crystal structures, biochemical and biophysical analyses, and computational simulations, we found that Gly463 plays an important role in the dynamics of ThrRS. Mutating this flexible residue into more rigid residues did not damage the enzyme's three-dimensional structure but significantly improved the thermal stability of the enzyme and suppressed its ability to change conformation. These mutations cause resistance of ThrRS to antibiotics that are conformationally selective, such as OB and borrelidin. This work not only elucidates the molecular mechanism of the self-resistance of OB-producing Pseudomonas fluorescens but also emphasizes the importance of backbone kinetics for aminoacyl-tRNA synthetase-targeting drug development.

PubMed: 39014102
DOI: 10.1038/s42003-024-06559-x

実験手法

X-RAY DIFFRACTION (3.08 Å)