4K86

Crystal structure of human prolyl-tRNA synthetase (apo form)

4K86 の概要

• エントリーDOI: 10.2210/pdb4k86/pdb
• 関連するPDBエントリー: 4K87 4K88
• 分子名称: Proline--tRNA ligase, ZINC ION (3 entities in total)
• 機能のキーワード: class ii trna synthetase, ligase, zinc binding, cytosol
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60613.51

構造登録者

Hwang, K.Y.,Son, J.H.,Lee, E.H. (登録日: 2013-04-18, 公開日: 2013-10-09, 最終更新日: 2023-11-08)

主引用文献

Son, J.,Lee, E.H.,Park, M.,Kim, J.H.,Kim, J.,Kim, S.,Jeon, Y.H.,Hwang, K.Y.
Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone.
Acta Crystallogr.,Sect.D, 69:2136-2145, 2013

PubMed Abstract: Aminoacyl-tRNA synthetases recognize cognate amino acids and tRNAs from their noncognate counterparts and catalyze the formation of aminoacyl-tRNAs. Halofuginone (HF), a coccidiostat used in veterinary medicine, exerts its effects by acting as a high-affinity inhibitor of the enzyme glutamyl-prolyl-tRNA synthetase (EPRS). In order to elucidate the precise molecular basis of this inhibition mechanism of human EPRS, the crystal structures of the prolyl-tRNA synthetase domain of human EPRS (hPRS) at 2.4 Å resolution (hPRS-apo), of hPRS complexed with ATP and the substrate proline at 2.3 Å resolution (hPRS-sub) and of hPRS complexed with HF at 2.62 Å resolution (hPRS-HF) are presented. These structures show plainly that motif 1 functions as a cap in hPRS, which is loosely opened in hPRS-apo, tightly closed in hPRS-sub and incorrectly closed in hPRS-HF. In addition, the structural analyses are consistent with more effective binding of hPRS to HF with ATP. Mutagenesis and biochemical analysis confirmed the key roles of two residues, Phe1097 and Arg1152, in the HF inhibition mechanism. These structures will lead to the development of more potent and selective hPRS inhibitors for promoting inflammatory resolution.

PubMed: 24100331
DOI: 10.1107/S0907444913020556

実験手法

X-RAY DIFFRACTION (2.4 Å)