Structural insight to human Retinoid X receptor alpha-Thyroid hormone receptor beta heterodimer by molecular modelling and MD-simulation studies: role of conserved water molecules

Abstract

The Retinoid X receptor alpha–Thyroid hormone receptor beta (RXRα-THRβ) 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 RXRα-THRβ 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 THRβ 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 THRβ structure.

Communicated by Ramaswamy H. Sarma

Keywords:

• Nuclear receptor
• thyroid hormone receptor
• Retenoid-X receptor
• conserved water molecules
• molecular dynamics simulation

Acknowledgements

SM, UA, and SSP thank to National Institute of Technology, Durgapur, for providing research facility in the Department of Chemistry. UA acknowledges SERB Govt. of India Sanction Order No. EMR/2017/005506 for computational facility.

Disclosure statement

The authors declare no competing interests.

Funding

UA acknowledges SERB Govt. of India Sanction Order No. EMR/2017/005506 for computational facility.

Author contribution

SM and SD designed, performed the experiments, analysed the data, and wrote the manuscript. UA and SSP were in charge of overall direction, planning, and supervised the project.

Availability of data and material

Data are available from authors upon request.