Molecular dynamics simulations on ROR?t: insights into its functional agonism and inverse agonism.

ABSTRACT: The retinoic acid receptor-related orphan receptor (ROR) ?t receptor is a member of nuclear receptors, which is indispensable for the expression of pro-inflammatory cytokine IL-17. ROR?t has been established as a drug target to design and discover novel treatments for multiple inflammatory and immunological diseases. It is important to elucidate the molecular mechanisms of how ROR?t is activated by an agonist, and how the transcription function of ROR?t is interrupted by an inverse agonist. In this study we performed molecular dynamics simulations on four different ROR?t systems, i.e., the apo protein, protein bound with agonist, protein bound with inverse agonist in the orthosteric-binding pocket, and protein bound with inverse agonist in the allosteric-binding pocket. We found that the orthosteric-binding pocket in the apo-form ROR?t was mostly open, confirming that apo-form ROR?t was constitutively active and could be readily activated (ca. tens of nanoseconds scale). The tracked data from MD simulations supported that ROR?t could be activated by an agonist binding at the orthosteric-binding pocket, because the bound agonist helped to enhance the triplet His479-Tyr502-Phe506 interactions and stabilized H12 structure. The stabilized H12 helped ROR?t to form the protein-binding site, and therefore made the receptor ready to recruit a coactivator molecule. We also showed that transcription function of ROR?t could be interrupted by the binding of inverse agonist at the orthosteric-binding pocket or at the allosteric-binding site. After the inverse agonist was bound, H12 either structurally collapsed, or reorientated to a different position, at which the presumed protein-binding site was not able to be formed.

SUBMITTER: Yuan CM 

PROVIDER: S-EPMC6961238 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature