脂肪酸硫酶A结晶结构由129个片段结合,提供了多样化的发展机会
Ekaterina Kot1, Matteo Paolo Ferla1, Patricia Helen Hollinshead2
1Centre for Medicines Discovery, Oxford, UK.
为了对抗除草剂耐药性,研究人员确定了针对脂肪酸化酶 (FATs) 的新型化学化合物. 碎片选揭示了强大的抑制剂,其中一个显示出显著的亲和力改善,为新的除草剂开发铺平了道路.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 农业化学品 农业化学品 农业化学品
背景情况:
- 抗除草剂耐药性需要多样化除草剂的作用模式.
- 脂肪酸化酶 (FATs) 是一个有希望的,未充分利用的目标,调节脂肪酸生物合成.
- 抑制脂肪会影响植物生长和生育能力.
研究的目的:
- 通过结晶学碎片选来识别针对脂肪的新型化学物质.
- 为了使Fata成为合理药物开发的目标.
主要方法:
- 在Arabidopsis thaliana FatA.的晶体学碎片选.
- 在1.5 Å分辨率下确定FatA的结构.
- 生物物理和生物化学测定用于目标验证.
主要成果:
- 确定了129个独特的碎片,在141种姿势中与FatA结合.
- 十个碎片显示出显著的功效,其中两个模仿已知的除草剂相互作用.
- 优化碎片亲和度从~20μm提高到~90nm KD.
- 结构分析显示,碎片诱导基质结合部位的形状变化.
结论:
- FatA 已被验证为成功开发的目标.
- 碎片击中提供了针对活跃和模态站点的新型支架.
- 这些发现加速了替代除草剂的开发,以解决耐药性问题.
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