Background: Thyroid hormone disrupting chemicals (THDCs) which are present in the environment, food and everyday consumer products, interfere with thyroid hormone signaling, possibly by interacting with thyroid hormone receptors (THRs). This alters the thyroid hormone homeostasis and affects various functions regulated by the thyroid hormone e.g. macronutrient metabolism, cardiovascular function, and normal brain development. Therefore, there is a necessity for detection and monitoring these pollutants in the environment. THRs belong to the nuclear receptor superfamily and have two highly conserved domains: DNA binding domain (DBD) and ligand binding domain (LBD). The LBD is responsible for the ligand selectivity and could be used as a bio-recognition element in a protein-based biosensor for THDCs detection. However, mutant LBD with increased affinity will act as better bio-recognition elements due to their increased sensitivity towards THDCs and capability in detecting very low quantities of chemicals.
Aim: Prediction of functionally important residues from the LBD of thyroid hormone receptor for rational modification to achieve high binding affinity.
Methods: Multiple sequence alignments of LBD of thyroid hormone receptor across the species were carried out to locate the differentially conserved alignment positions. By employing information theoretic measures (Cumulative Relative Entropy (CRE)) we tried to present a structural and functional analysis of LBD of thyroid hormone receptors. Since THR belongs to thyroid-hormone like a family of nuclear receptor superfamily, we contrasted THR with estrogen receptors (ER). CRE was calculated for two sets of alignments.
Results: Based on highest CRE scoring twenty positions were selected and predicted to impart functional specificity to THR as well as other TH-like receptors.
Conclusion/Significance: Selected residues could be used for rational design of LBD with an enhanced affinity towards ligands and applied towards the development of sensitive protein-based biosensors to detect THDCs.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology