期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 41, 期 19, 页码 9828-9839出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2022.2147097
关键词
Nuclear receptor; thyroid hormone receptor; Retenoid-X receptor; conserved water molecules; molecular dynamics simulation
The RXR alpha-THR beta heterodimer plays a crucial role in human growth and development. This heterodimer interacts with DNA through conserved/semiconserved water molecules, which mediate the interaction between amino acid residues and DNA sequences.
The Retinoid X receptor alpha-Thyroid hormone receptor beta (RXR alpha-THR beta) heterodimer plays an important role in physiological function of humans specially in the growth and development. Extensive MD-simulation studies on the aquated complexes of modelled RXR alpha-THR beta heterodimer with DNA-duplex have indicated the role of some conserved/semiconserved water molecules in the complexation process in presence or absence of Triiodothyronine (T3) and 9-cis retinoic acid (9CR) in the respective Ligand Binding Domain (LBD) domain. Among the seventeen conserved/semi-conserved water molecules, the W1-W4 water centers have been observed to mediate the interaction between the residues of A-chain (DBD of RXR) to consensus sequence (C-chain) of DNA. The W5-W8 water centers involve in recognition of the residues of B-chain (DBD of THR) to C-chain of DNA. The W9-W13 centers have connected the different residues of B-chain (THR) to D-chain of DNA through H-bonds, whereas W14-W17 water molecules were involved in the interaction of A-chain(')s (RXR) residues to D-chain of DNA. In our previous study with homodimeric THR beta from Rattus norvegicus we have identified fifteen conserved water molecules at the DNA-DBD interface. Moreover, the conformational flexibility of Met313 (in the LBD of THR) from open to close form in presence or absence of T3 molecule in the holo and Apo-protein may provide a plausible rational on the possible role of that residue to acts as gate which could restrict the solvent molecules to enter into the hydrophobic T3-binding pocket of LBD during the absence of ligand molecule and thus could help the stabilization of that domain in THR beta structure.Communicated by Ramaswamy H. Sarma
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