Elucidation of the mechanism of partial activation of EPAC1 allosteric modulators by Markov state modelling.

ABSTRACT: The development of selective modulators of exchange protein activated by cAMP (EPAC1/RAPGEF3) would pave the way for novel therapeutic interventions in cardiac, metabolic, inflammatory, and oncologic disorders. Here we have applied a computational workflow using Markov State Models (MSMs) and steered molecular dynamics (sMD) to probe the allosteric activation of EPAC1 by both cAMP and pharmaceutical hit compound I942. sMD was used to examine the large-scale domain rearrangement EPAC1 undergoes during activation. Intermediate conformations accessed via sMD were then used as starting points for equilibrium MD simulations, which were pooled for the construction of MSMs. The resulting models capture the activation of wild-type (WT) EPAC1 by cAMP, and provide an explanation for the lack

SUBMITTER: Hardie A 

PROVIDER: S-EPMC12268604 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature