AI Article Synopsis
- The research focuses on the thyroxine receptor beta (TRβ), a nuclear receptor crucial for lipid metabolism and a key target for treating nonalcoholic steatohepatitis (NASH).
- MGL-3196 (Resmetirom) is the first TRβ agonist to show success in phase III clinical trials for NASH, making its mechanism of action an important area of study.
- The study employs molecular dynamic simulations to analyze how MGL-3196 interacts with TRβ and finds that specific mutations (R243Q and H435R) can make TRβ unresponsive to MGL-3196, potentially affecting treatment outcomes for NASH patients with these mutations.
Article Abstract
Thyroxine receptor beta (TRβ) is a ligand-dependent nuclear receptor that participates in regulating multiple biological processes, particularly playing an important role in lipid metabolism regulation. TRβ is currently a popular therapeutic target for nonalcoholic steatohepatitis (NASH), while no drugs have been approved to treat this disease. MGL-3196 (Resmetirom) is the first TRβ agonist that has succeeded in phase III clinical trials for the treatment of NASH; therefore, studying its molecular mechanism of action is of great significance. In this study, we employed molecular dynamic simulation to investigate the interaction mode between MGL-3196 and TRβ at the all-atom level. More importantly, by comparing the binding patterns of MGL-3196 in several prevalent TRβ mutants, it was identified that the mutations R243Q and H435R located, respectively, around and within the ligand-binding pocket of TRβ cause TRβ to be insensitive to MGL-3196. This indicates that patients with NASH carrying these two mutations may exhibit resistance to the medication of MGL-3196, thereby highlighting the potential impact of TRβ mutations on TRβ-targeted treatment of NASH and beyond.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097192 | PMC |
| http://dx.doi.org/10.1021/acsomega.4c00089 | DOI Listing |
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