ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Oxford OX3 7FZ, UK.
ARUK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, Old Road Campus, University of Oxford, Oxford OX3 7FZ, UK.
Structure. 2024 Apr 4;32(4):453-466.e6. doi: 10.1016/j.str.2024.01.005. Epub 2024 Feb 2.
SHIP1, an inositol 5-phosphatase, plays a central role in cellular signaling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics on SHIP1 and SHIP2. Our findings demonstrate that the influence of the C2 domain is more pronounced for SHIP2 than SHIP1. We determined 91 structures of SHIP1 with fragments bound, with some near the interface between the two domains. We performed a mass spectrometry screen and determined four structures with covalent fragments. These structures could act as starting points for the development of potent, selective probes.
SHIP1 是一种肌醇 5-磷酸酶，在细胞信号转导中起着核心作用。因此，它与许多疾病有关。利用 SHIP1 作为药物靶点需要结构知识和选择性小分子的设计。我们已经确定了 SHIP1 的磷酸酶和 C2 结构域的无配位、镁配位和磷酸盐配位结构。SHIP1 和相关的 SHIP2 的 C2 结构域调节磷酸酶结构域的活性。为了理解这一机制，我们对 SHIP1 和 SHIP2 进行了活性测定、氢氘交换质谱和分子动力学分析。我们的研究结果表明，C2 结构域对 SHIP2 的影响比 SHIP1 更明显。我们结合片段确定了 91 个 SHIP1 结构，其中一些结构靠近两个结构域的界面。我们进行了质谱筛选，并确定了四个具有共价片段的结构。这些结构可以作为开发有效、选择性探针的起点。
