The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

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• 作者：Alexander K. Clark ; J. Heath Wilder ; Aaron W. Grayson ; Quentin R. Johnson ; Richard J. Lindsay ; Ricky B. Nellas ; Elias J. Fernandez ; Tongye Shen
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：120
• 期：33
• 页码：8338-8345
• 全文大小：423K
• 年卷期：0
• ISSN：1520-5207

文摘

The promiscuous protein retinoid X receptor (RXR) displays essential allosteric regulation of several members in the nuclear hormone receptor superfamily via heterodimerization and (anti)cooperative binding of cognate ligands. Here, the structural basis of the positive allostery of RXR and constitutive androstane receptor (CAR) is revealed. In contrast, a similar computational approach had previously revealed the mechanism for negative allostery in the complex of RXR and thyroid receptor (TR). By comparing the positive and negative allostery of RXR complexed with CAR and TR respectively, we reported the promiscuous allosteric control involving RXR. We characterize the allosteric mechanism by expressing the correlated dynamics of selected residue–residue contacts which was extracted from atomistic molecular dynamics simulation and statistical analysis. While the same set of residues in the binding pocket of RXR may initiate the residue–residue interaction network, RXR uses largely different sets of contacts (only about one-third identical) and allosteric modes to regulate TR and CAR. The promiscuity of RXR control may originate from multiple factors, including (1) the frustrated fit of cognate ligand 9c to the RXR binding pocket and (2) the different ligand-binding features of TR (loose) versus CAR (tight) to their corresponding cognate ligands.