scholarly journals Constant velocity pulling and unfolding of thyroid hormone receptor by steered molecular dynamics

BIBECHANA ◽  
2020 ◽  
Vol 17 ◽  
pp. 50-57
Author(s):  
Tika Ram Lamichhane ◽  
Hari Prasad Lamichhane
Keyword(s):  
Molecular Dynamics ◽  
Thyroid Hormone ◽  
Ligand Binding ◽  
Hormone Receptor ◽  
Constant Velocity ◽  
Thyroid Hormone Receptor ◽  
Steered Molecular Dynamics ◽  
Electrostatic Energy ◽  
Gene Expressions ◽  
Globular Form

Unfolding pathways of T3 liganded thyroid hormone receptor (THRT3) can be studied by using the protocols of steered molecular dynamics (SMD). Theory of constant velocity pulling has been implemented to the structure of THRT3 in a neutral water-ion solution equilibrated up to 20 ns. The globular form of THRT3 is completely unfolded extending N-C termini from 38 Å to 876 Å at a constant speed of 0.1 Å/ps by means of 8.5 ns long SMD simulations. The peak force measured in the intermediate conformations is related to a burst of backbone H-bonds among a-helices and b-hairpins. With decrease in H-bonds, electrostatic energy increases by losing gradually the secondary structure and separating a and b-strands in solution. The force at the end (t > 8.5 ns) increases steeply with the large increase in bond-angle and bond-length potentials when the system becomes completely unfolded. The hydrophobic ligand binding domain (LBD) of THR-b with load bearing H-bonds protects T3 from water attack.  Even after complete unfolding of THR-b LBD, the position of T3 is not deviated more than 2.5 Å and a large number of water molecules remain in the surrounding of this domain area. This is a strong evidence for the mechanochemical stability of a receptor protein’s LBD towards hormone activated gene expressions followed by ligand binding and dissociation. BIBECHANA 17 (2020) 50-57

Helix 12 Dynamics and Thyroid Hormone Receptor Activity: Experimental and Molecular Dynamics Studies of Ile280 Mutants

2011 ◽  
Vol 412 (5) ◽  
pp. 882-893 ◽  
Author(s):  
Paulo C.T. Souza ◽  
Gustavo B. Barra ◽  
Lara F.R. Velasco ◽  
Isabel C.J. Ribeiro ◽  
Luiz A. Simeoni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Receptor Activity ◽  
Helix 12

scholarly journals Functional Evidence for Retinoid X Receptor (RXR) as a Nonsilent Partner in the Thyroid Hormone Receptor/RXR Heterodimer

2002 ◽  
Vol 22 (16) ◽  
pp. 5782-5792 ◽  
Author(s):  
Dangsheng Li ◽  
Tong Li ◽  
Fang Wang ◽  
Heather Tian ◽  
Herbert H. Samuels
Keyword(s):  
Thyroid Hormone ◽  
Ligand Binding ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Retinoid Receptor ◽  
Peroxisome Proliferator Activated Receptor

ABSTRACT Many members of the thyroid hormone/retinoid receptor subfamily (type II nuclear receptors) function as heterodimers with the retinoid X receptor (RXR). In heterodimers which are referred to as permissive, such as peroxisome proliferator activated receptor/RXR, both partners can bind cognate ligands and elicit ligand-dependent transactivation. In contrast, the thyroid hormone receptor (TR)/RXR heterodimer is believed to be nonpermissive, where RXR is thought to be incapable of ligand binding and is often referred to as a silent partner. In this report, we used a sensitive derepression assay system that we developed previously to reexamine the TR/RXR interrelationship. We provide functional evidence suggesting that in a TR/RXR heterodimer, the RXR component can bind its ligand in vivo. Ligand binding by RXR does not appear to directly activate the TR/RXR heterodimer; instead, it leads to a (at least transient or dynamic) dissociation of a cellular inhibitor(s)/corepressor(s) from its TR partner and thus may serve to modulate unliganded TR-mediated repression and/or liganded TR-mediated activation. Our results argue against the current silent-partner model for RXR in the TR/RXR heterodimer and reveal an unexpected aspect of cross regulation between TR and RXR.

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