The effect of ligand affinity to the contact dynamics of the ligand binding domain of thyroid hormone receptor - retinoid X receptor
| Autor: | Mac Kevin E. Braza, Ricky B. Nellas, James Peter L. Lim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Receptors Retinoic Acid Allosteric regulation Retinoic acid Retinoid X receptor Ligands 010402 general chemistry 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Gene expression Materials Chemistry Physical and Theoretical Chemistry Spectroscopy Receptors Thyroid Hormone Thyroid hormone receptor Triiodothyronine Ligand Protein dynamics Computer Graphics and Computer-Aided Design 0104 chemical sciences Retinoid X Receptors 030104 developmental biology chemistry Biophysics |
| Zdroj: | Journal of Molecular Graphics and Modelling. 104:107829 |
| ISSN: | 1093-3263 |
| DOI: | 10.1016/j.jmgm.2020.107829 |
| Popis: | Ligand-based allostery has been gaining attention for its importance in protein regulation and implication in drug design. One of the interesting cases of protein allostery is the thyroid hormone receptor - retinoid x receptor (TR:RXR), which regulates the gene expression of important physiological processes, such as development and metabolism. It is regulated by the TR native ligand triiodothyronine (T3), which displays anticooperative behavior to the RXR ligand 9-cis retinoic acid (9C). In contrast to this anticooperative behavior, 9C has been shown to increase the activity of TR:RXR. Here we probed the influence of the affinity and the interactions of the TR ligand to the allostery of the TR:RXR through contact dynamics and residue networks. The TR ligand analogs were designed to have higher (G2) and lower (N1) binding energies than T3 when docked to the TR:RXR(9C) complex. The aqueous TR(N1/T3/G2):RXR(9C) complexes were subjected to 30 ns all-atom simulations using theNAMD. The program CAMERRA was used to capture the subtle perturbations of TR:RXR by mapping the residue contact dynamics. Various parts of the TR ligands; including the hydrophilic head, the iodine substituents, and the ligand tail; have been probed for their significance in ligand affinity. The results on the T3 and G2 complexes suggest that ligand affinity can be utilized as a predictor for anticooperative systems on which ligand is more likely to dissociate or remain bound. All 3 complexes also display distinct contact networks for cross-dimer signalling and ligand communication. Understanding ligand-based allostery could potentially unveil secrets of ligand-regulated protein dynamics, a foundation for the design of better and more efficient allosteric drugs. |
| Databáze: | OpenAIRE |
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