Cyclopamine modulates smoothened receptor activity in a binding position dependent manner.

ABSTRACT: Cyclopamine, a natural alkaloid, can act as an agonist when it binds to the Cysteine-Rich Domain (CRD) of Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explore the dynamic behavior of cyclopamine's interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower free energy barrier of ~2 kcal/mol, and expansion of hydrophobic tunnel to facilitate cholesterol transport agrees wit

SUBMITTER: Kim K 

PROVIDER: S-EPMC11438977 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature