文献类型：期刊文献

英文题名：SNP mutations occurring in thyroid hormone receptor influenced individual susceptibility to triiodothyronine: Molecular dynamics and site-directed mutagenesis approaches

作者：Liu, Yaquan[1];Qu, Kaili[1];Hai, Ying[1];Li, Xin[2];Zhao, Lei[3];Zhao, Chunyan[1]

第一作者：Liu, Yaquan

通信作者：Zhao, CY[1]

机构：[1]Lanzhou Univ, Sch Pharm, Lanzhou 730000, Gansu, Peoples R China;[2]Henan Univ Sci & Technol, Coll Food & Bioengn, Luoyang, Peoples R China;[3]Gansu Univ Chinese Med, Univ Gansu Prov, Key Lab Chem & Qual Tradit Chinese Med, Lanzhou, Gansu, Peoples R China

第一机构：Lanzhou Univ, Sch Pharm, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Sch Pharm, Lanzhou 730000, Gansu, Peoples R China.

年份：2018

卷号：119

期号：3

起止页码：2604

外文期刊名：JOURNAL OF CELLULAR BIOCHEMISTRY

收录：;Scopus(收录号：2-s2.0-85040975437);WOS:【SCI-EXPANDED(收录号:WOS:000423396200015)】；

基金：National Natural Science Foundation of China, Grant numbers: No. 31000017, No. 21207056; State Key Laboratory of Environmental Chemistry and Ecotoxicology; Research Center for EcoEnvironmental Sciences, Chinese Academy of Sciences, Grant number: KF2015-17; Key Laboratory of Chemistry and Quality for Traditional Chinese Medicines of the University of Gansu Province, Gansu University of Chinese Medicines, Grant number: zzy-2016-01; Fundamental Research Funds for the Central Universities, Grant numbers: lzujbky2017-200, lzujbky-2017-kb05, LZUJZH1914; Gansu Provincial Administration of traditional Chinese Medicine, Grant number: GZK-2017-63; Lanzhou Talent Innovation and Entrepreneurship Technology Program, Grant number: 2016-RC-19.

语种：英文

外文关键词：fluorescence analysis; molecular dynamic; single-nucleotide polymorphisms; site-directed mutagenesis; thyroid hormone receptor

摘要：The increasing evidences have suggested that expression of single nucleotide polymorphisms (SNP) coded thyroid hormone receptors (THR) generally are associated with individual susceptibility to chemicals. In the present research, multiple molecular dynamics simulations on four SNP mutants (G332R, T337, G345R, and G347E) were performed to investigate the structural and dynamical altering, which could lead to a binding capability variation to triiodothyronine (T3). It proved the structures of two SNP mutants (G345R and T337) occurring in the THR proteins had experienced conformational change to a great extend, which also led to a significant decreasing in binding ability with T3. In addition, two mutates (G345R and G347E) and wild type THR proteins were expressed and purified based on site-directed mutagenesis technology to test their binding abilities with T3 by fluorescence experiments. The fluorescence quenching efficiencies of two mutates displayed that the conjugation with T3 decreased with a significant rate in G345R system and a little rate in G347E system compared with its wild type. It was consistent with the molecular dynamic research that the SNP mutations did change structures of THR protein, and thereby decreased the binding behavior of T3 at different extent. The overall molecular-level look at the protein structure may provide the structural basis to explain how one amino acid change can create a ripple effect on the protein structures and eventually affect the binding affinity of the ligands, which maybe the first stage to understand how SNP mutation results in individual difference in susceptibility to variant chemicals.