7zau
Fascin-1 in complex with Nb 3E11
Structural highlights
FunctionFSCN1_HUMAN Organizes filamentous actin into bundles with a minimum of 4.1:1 actin/fascin ratio. Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers. Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration.[1] [2] [3] [4] Publication Abstract from PubMedFascin-1-mediated actin-bundling activity is central to the generation of plasma membrane protrusions required for cell migration. Dysregulated formation of cellular protrusions is observed in metastatic cancers, where they are required for increased invasiveness, and is often correlated with increased Fascin-1 abundance. Therefore, there is interest in generating therapeutic Fascin-1 inhibitors. We present the identification of Nb 3E11, a nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation. The crystal structure of the Fascin-1/Nb 3E11 complex reveals the structural mechanism of inhibition. Nb 3E11 occludes an actin-binding site on the third beta-trefoil domain of Fascin-1 that is currently not targeted by chemical inhibitors. Binding of Nb 3E11 to Fascin-1 induces a conformational change in the adjacent domains to stabilize Fascin-1 in an inhibitory state similar to that adopted in the presence of small-molecule inhibitors. Nb 3E11 could be used as a tool inhibitor molecule to aid in the development of Fascin-1 targeted therapeutics. A nanobody inhibitor of Fascin-1 actin-bundling activity and filopodia formation.,Burgess SG, Paul NR, Richards MW, Ault JR, Askenatzis L, Claydon SG, Corbyn R, Machesky LM, Bayliss R Open Biol. 2024 Mar;14(3):230376. doi: 10.1098/rsob.230376. Epub 2024 Mar 20. PMID:38503329[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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