瘤消亡因子α的活性由动态形态重组调节
Daniela Hofmann1, Loïc Salmon1, Gerhard Wider1
1Institute of Molecular Biology and Biophysics, ETH Zürich , 8093 Zürich, Switzerland.
Journal of the American Chemical Society
|December 2, 2017
概括
使用NMR研究了瘤死因α (TNFα) 的失活. 干扰TNFα接口增加了它的动力,为向炎症疾病提供了新的策略.
科学领域:
- 生物化学
- 免疫学
- 结构生物学
背景情况:
- 瘤死因α (TNFα) 是一种调节免疫反应的关键细胞因子.
- 失调的TNFα活性与主要的慢性炎症疾病有关.
- 通过破坏其蛋白质-蛋白质接口来禁用TNFα是一种治疗策略,但其机制尚不清楚.
研究的目的:
- 阐明TNFα失活的原子分辨机制.
- 研究活性和非活性TNFα的溶液结构和动态.
- 了解接口扰动如何影响TNFα结构和动态.
主要方法:
- 核磁共振 (NMR) 光谱检测溶液结构和动态.
- 在三元化界面的残留物定位突变.
- 使用低分子量抑制剂向TNFα接口.
主要成果:
- TNFα在各种时间尺度上表现出运动.
- 干扰TNFα接口并没有改变其整体结构或三元体状态.
- 失活导致从接口到受体结合区域的形态动态增加.
结论:
- TNFα无活化涉及结构动态的增加而不是完整的结构崩.
- 这些发现为TNFα失活提供了机理性见解.
- 这项研究为开发针对炎症性疾病TNFα活性的新策略奠定了基础.
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