Nuffield Department of Medicine, Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, Oxford, United Kingdom.
Nuffield Department of Medicine, Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, Centre for Medicines Discovery, University of Oxford, Oxford, United Kingdom; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom; Department of Biochemistry, University of Johannesburg, Auckland Park, South Africa.
J Biol Chem. 2021 Jan-Jun;296:100521. doi: 10.1016/j.jbc.2021.100521. Epub 2021 Mar 5.
The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK subfamilies. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small-molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes.
人类胞质分裂的奉献者（DOCK）家族由 11 种结构上保守的蛋白质组成，它们作为非典型的 RHO 鸟苷三磷酸酶（RHO GEF）发挥作用。这些调节蛋白作为众多细胞级联反应的介质，促进细胞骨架重塑，在神经元的分化、迁移、极化和轴突生长等各种关键过程中发挥作用。在分子水平上，DOCK DHR2 结构域促进从小 GTP 酶中解离核苷酸，否则这个过程对于快速时空控制细胞信号转导来说太慢了。在这里，我们提供了各种 DOCK 蛋白的生物学和结构特征概述，并描述了它们与其他 RHO GEF 之间的区别以及 DOCK 亚家族之间的区别。该家族的表达因细胞或组织类型而异，因此它们与广泛的疾病表型有关，特别是在大脑中。越来越多的可用结构信息揭示了催化 DHR2 结构域引发核苷酸解离的机制，并指出了发现和设计高亲和力小分子抑制剂的策略。这些化合物可以作为化学探针来研究细胞功能，并为这类重要酶的药物发现提供起点。
