Exploring the Allosteric\nResponse of Fascin to Its\nInhibitor

Fascin is a major actin-binding protein (ABP) for stabilizing\nfilopodia\nto support efficient adhesion and migration of cancer cells. Fascin\nis also highly expressed in metastatic tumors. Disrupting the actin-binding\nsite (ABS) on fascin constitutes a critical approach to hindering\ntumor metastasis. The G2 series of small molecules was formulated\nwith the specific purpose of obstructing the binding pocket of fascin.\nThe determination of inhibitor-induced structural dynamics in fascin\nis crucial for a comprehensive of its biological functions and the\nstrategic development of pharmacological interventions. In this study,\nwe utilized both equilibrium and dynamical-nonequilibrium molecular\ndynamics (D-NEMD) to elucidate the molecular mechanisms responsible\nfor transmitting structural changes when removing the G2 inhibitor,\nin both the wild type (WT) and its variants. Our findings indicate\nthat when G2 is removed, structural dynamics in fascin originate from\nthe G2 binding pocket of fascin and propagate signals through the\nconformational transformation that spans all four β-trefoil\ndomains. Although different mutant variants demonstrated comparable\nconformational networks, they showed varying response times. However,\nthe signaling pathways in mutants remained consistent in comparison\nto the WT fascin. This study provides valuable insights into the structural\nfeatures and communication pathways of fascin and provides avenues\nfor the development of targeted inhibitors with promising prospects\nin cancer therapy.