Molecular dynamics simulations on RORγt: insights into its functional agonism and inverse agonism
| Autor: | Jun Xu, Cong-Min Yuan, Xiaojun Ma, Nannan Sun, Hai-Hong Chen, Wei Fu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Indazoles Drug Inverse Agonism Pyridines medicine.drug_class Retinoic acid Molecular Dynamics Simulation Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RAR-related orphan receptor gamma Coactivator medicine Humans Inverse agonist Anilides Pharmacology (medical) Receptor Pharmacology Orphan receptor General Medicine Nuclear Receptor Subfamily 1 Group F Member 3 Cell biology 030104 developmental biology chemistry Nuclear receptor 030220 oncology & carcinogenesis Allosteric Site Protein Binding |
| Zdroj: | Acta Pharmacol Sin |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/s41401-019-0259-z |
| Popis: | The retinoic acid receptor-related orphan receptor (ROR) γt receptor is a member of nuclear receptors, which is indispensable for the expression of pro-inflammatory cytokine IL-17. RORγt 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 RORγt is activated by an agonist, and how the transcription function of RORγt is interrupted by an inverse agonist. In this study we performed molecular dynamics simulations on four different RORγt 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 RORγt was mostly open, confirming that apo-form RORγt was constitutively active and could be readily activated (ca. tens of nanoseconds scale). The tracked data from MD simulations supported that RORγt 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 RORγt to form the protein-binding site, and therefore made the receptor ready to recruit a coactivator molecule. We also showed that transcription function of RORγt 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. |
| Databáze: | OpenAIRE |
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