7ZOG

Crystal structure of Cryptosporidium parvum -Plasmodium falciparum mutant lysyl tRNA synthetase in complex with inhibitor

7ZOG の概要

• エントリーDOI: 10.2210/pdb7zog/pdb
• 分子名称: Lysine-tRNA ligase, LYSINE, 8-[[4-[2-[2-[2-[2-[(azanylidene-$l^{4}-azanylidene)amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]sulfonylamino]-~{N}-(cyclohexylmethyl)-6-fluoranyl-4-oxidanylidene-chromene-2-carboxamide, ... (5 entities in total)
• 機能のキーワード: trna binding, ligase
• 由来する生物種: Cryptosporidium parvum Iowa II
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 249812.81

構造登録者

Dawson, A.,Wyllie, S. (登録日: 2022-04-25, 公開日: 2022-09-07, 最終更新日: 2024-06-19)

主引用文献

Milne, R.,Wiedemar, N.,Corpas-Lopez, V.,Moynihan, E.,Wall, R.J.,Dawson, A.,Robinson, D.A.,Shepherd, S.M.,Smith, R.J.,Hallyburton, I.,Post, J.M.,Dowers, K.,Torrie, L.S.,Gilbert, I.H.,Baragana, B.,Patterson, S.,Wyllie, S.
Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.
Acs Infect Dis., 8:1962-1974, 2022

PubMed Abstract: There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (KRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages.

PubMed: 36037410
DOI: 10.1021/acsinfecdis.2c00364

実験手法

X-RAY DIFFRACTION (1.8 Å)