Department of Comparative Biomedical Science, Royal Veterinary College, Royal College Street, London, U.K.
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, U.K.
Biochem J. 2021 Jul 30;478(14):2945-2951. doi: 10.1042/BCJ20210383.
Since the discovery of mutations in leucine-rich repeat kinase 2 (LRRK2) as an underlying genetic cause for the development of Parkinson's disease (PD) in 2004 (Neuron 44, 601-607; Neuron 44, 595-600), and subsequent efforts to develop LRRK2 kinase inhibitors as a therapy for Parkinson's (Expert Opin. Ther. Targets 21, 751-753), elucidating the atomic resolution structure of LRRK2 has been a major goal of research into this protein. At over 250 kDa, the large size and complicated domain organisation of LRRK2 has made this a highly challenging target for structural biologists, however, a number of recent studies using both in vitro and in situ approaches (Nature 588, 344-349; Cell 182, 1508-1518.e1516; Cell 184, 3519-3527.e3510) have provided important new insights into LRRK2 structure and the complexes formed by this protein.
自 2004 年发现富含亮氨酸重复激酶 2（LRRK2）突变是帕金森病（PD）发展的潜在遗传原因以来（神经元 44,601-607；神经元 44,595-600），以及随后努力开发 LRRK2 激酶抑制剂作为帕金森病的治疗方法（专家意见。治疗目标 21,751-753），阐明 LRRK2 的原子分辨率结构一直是该蛋白研究的主要目标。LRRK2 的分子量超过 250 kDa，其庞大的尺寸和复杂的结构域组织使得这一目标对结构生物学家来说极具挑战性，然而，最近的一些使用体外和原位方法的研究（自然 588,344-349；细胞 182,1508-1518.e1516；细胞 184,3519-3527.e3510）为 LRRK2 结构以及该蛋白形成的复合物提供了重要的新见解。
