期刊
ISCIENCE
卷 20, 期 -, 页码 489-+出版社
CELL PRESS
DOI: 10.1016/j.isci.2019.10.002
关键词
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资金
- National Natural Science Foundation of China [31770814]
- Programme of Introducing Talents of Discipline to Universities [B06016]
- National Science Foundation of China for Fostering Talents in Basic Research [J1310027]
Resistance to thyroid hormone (RTH) is a clinical disorder without specific and effective therapeutic strategy, partly due to the lack of structural mechanisms for the defective ligand binding by mutated thyroid hormone receptors (THRs). We herein uncovered the prescription drug roxadustat as a novel THRb-selective ligand with therapeutic potentials in treating RTH, thereby providing a small molecule tool enabling the first probe into the structural mechanisms of RTH. Despite a wide distribution of the receptor mutation sites, different THR beta mutants induce allosteric conformational modulation on the same His435 residue, which disrupts a critical hydrogen bond required for the binding of thyroid hormones. Interestingly, roxadustat retains hydrophobic interactions with THRb via its unique phenyl extension, enabling the rescue of the activity of the THRb mutants. Our study thus reveals a critical receptor allosterism mechanism for RTH by mutant THRb, providing a new and viable therapeutic strategy for the treatment of RTH.
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