美国圣裘德儿童研究医院Charalampos G. Kalodimos团队的论文发现激酶的动态构象决定其功能。该研究于2020年10月1日发表于《科学》。

研究人员使用核磁共振波谱法以原子级的细节描述了Abl激酶如何在一个活性构象和两个离散的非活性构象之间相互转化。构象状态之间关键结构元素的广泛差异引起了多种内在调节机制。这些发现解释了致癌突变体如何消除组成性激活激酶的抑制机制。

高效的解剖揭示了激活环、DFG基序、调节型脊柱和门控残基对激酶调节的贡献。药物伊马替尼瞬时结合构象的表征能够阐明耐药机制。对非活性状态的结构解析突出了如何利用它们来设计选择性抑制剂。

研究人员表示，蛋白激酶从本质具有许多催化和结合活性的构象状态。

附：英文原文

Title: Conformational states dynamically populated by a kinase determine its function

Author: Tao Xie, Tamjeed Saleh, Paolo Rossi, Charalampos G. Kalodimos

Issue&Volume: 2020/10/01

Abstract: Protein kinases intrinsically sample a number of conformational states with distinct catalytic and binding activities. We used nuclear magnetic resonance spectroscopy to describe in atomic-level detail how Abl kinase interconverts between an active and two discrete inactive structures. Extensive differences in key structural elements among the conformational states give rise to multiple intrinsic regulatory mechanisms. The findings explain how oncogenic mutants can counteract inhibitory mechanisms to constitutively activate the kinase. Energetic dissection revealed the contribution of the activation loop, the DFG motif, the regulatory spine and the gatekeeper residue to kinase regulation. Characterization of the transient conformation to which the drug imatinib binds enabled the elucidation of drug resistance mechanisms. Structural insight into inactive states highlights how they can be leveraged for the design of selective inhibitors.

DOI: 10.1126/science.abc2754

Source: https://science.sciencemag.org/content/early/2020/09/30/science.abc2754