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.

Autor:	Mukherjee S; Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India., Dasgupta S; Department of Bioscience and Bioengineering, Indian Institute of Technology-Bombay, Mumbai, India., Panja SS; Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India., Adhikari U; Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India.
Jazyk:	angličtina
Zdroj:	Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2023 Nov; Vol. 41 (19), pp. 9828-9839. Date of Electronic Publication: 2022 Nov 21.
DOI:	10.1080/07391102.2022.2147097
Abstrakt:	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.
Databáze:	MEDLINE
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