Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors.

ABSTRACT: Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding proce

SUBMITTER: He X 

PROVIDER: S-EPMC7918825 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature