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RHO to the DOCK for GDP disembarking: structural insights into the DOCK GTPase nucleotide exchange factors

DOI: 10.1016/j.jbc.2021.100521 DOI Help

Authors: Andrew Thompson (Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford; Target Discovery Institute, University of Oxford) , Christina Bitsina (Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford; Target Discovery Institute, University of Oxford) , Janine L. Gray (Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford; Target Discovery Institute, University of Oxford) , Frank Von Delft (Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford; Diamond Light Source; University of Johannesburg) , Paul E. Brennan (Alzheimer’s Research UK Oxford Drug Discovery Institute, University of Oxford; Target Discovery Institute, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 24

State: Published (Approved)
Published: March 2021

Open Access Open Access

Abstract: 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 remodelling, playing roles in various crucial processes such as differentiation, migration, polarisation and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process which is otherwise too slow for rapid spatiotemporal control of cellular signalling. 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 sub-families. 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.

Journal Keywords: Dedicator of cytokinesis (DOCK); guanine nucleotide exchange factor; guanosine triphosphate (GTP); Ras homologous (RHO) small GTPases; cell signalling; structural biology; drug discovery

Diamond Keywords: Alzheimer's Disease

Subject Areas: Biology and Bio-materials, Medicine


Technical Areas:

Added On: 15/03/2021 13:03

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

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