Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family

BackgroundThe thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The TH...

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Main Authors: Sonia Verma, Soumyananda Chakraborti, Om P. Singh, Veena Pande, Rajnikant Dixit, Amit V. Pandey, Kailash C. Pandey
Format: Article
Language:English
Published: Frontiers Media S.A. 2022-09-01
Series:Frontiers in Endocrinology
Subjects:
Online Access:https://www.frontiersin.org/articles/10.3389/fendo.2022.981090/full
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author Sonia Verma
Sonia Verma
Sonia Verma
Soumyananda Chakraborti
Om P. Singh
Veena Pande
Rajnikant Dixit
Amit V. Pandey
Amit V. Pandey
Kailash C. Pandey
Kailash C. Pandey
author_facet Sonia Verma
Sonia Verma
Sonia Verma
Soumyananda Chakraborti
Om P. Singh
Veena Pande
Rajnikant Dixit
Amit V. Pandey
Amit V. Pandey
Kailash C. Pandey
Kailash C. Pandey
author_sort Sonia Verma
collection DOAJ
description BackgroundThe thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc.MethodsIn this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies.ResultsPhylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc.ConclusionOur study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors.
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spelling doaj.art-24149ac5374b4fb0a5a09993499b636e2023-03-09T17:31:02ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-09-011310.3389/fendo.2022.981090981090Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like familySonia Verma0Sonia Verma1Sonia Verma2Soumyananda Chakraborti3Om P. Singh4Veena Pande5Rajnikant Dixit6Amit V. Pandey7Amit V. Pandey8Kailash C. Pandey9Kailash C. Pandey10Parasite-Host Biology Group, ICMR-National Institute of Malaria Research, New Delhi, IndiaPediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital, Bern, SwitzerlandTranslational Hormone Research Cluster, Department of Biomedical Research, University of Bern, Bern, SwitzerlandParasite-Host Biology Group, ICMR-National Institute of Malaria Research, New Delhi, IndiaParasite-Host Biology Group, ICMR-National Institute of Malaria Research, New Delhi, IndiaKumaun University, Nainital, Uttrakhand, IndiaParasite-Host Biology Group, ICMR-National Institute of Malaria Research, New Delhi, IndiaPediatric Endocrinology, Diabetology, and Metabolism, University Children’s Hospital, Bern, SwitzerlandTranslational Hormone Research Cluster, Department of Biomedical Research, University of Bern, Bern, SwitzerlandParasite-Host Biology Group, ICMR-National Institute of Malaria Research, New Delhi, IndiaAcademy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, IndiaBackgroundThe thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc.MethodsIn this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies.ResultsPhylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc.ConclusionOur study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors.https://www.frontiersin.org/articles/10.3389/fendo.2022.981090/fullnuclear receptorthyroid hormone receptor-like familyligand-binding domainsequence conservationphylogenyrelative entropy
spellingShingle Sonia Verma
Sonia Verma
Sonia Verma
Soumyananda Chakraborti
Om P. Singh
Veena Pande
Rajnikant Dixit
Amit V. Pandey
Amit V. Pandey
Kailash C. Pandey
Kailash C. Pandey
Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
Frontiers in Endocrinology
nuclear receptor
thyroid hormone receptor-like family
ligand-binding domain
sequence conservation
phylogeny
relative entropy
title Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
title_full Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
title_fullStr Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
title_full_unstemmed Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
title_short Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family
title_sort recognition of fold and function specific sites in the ligand binding domain of the thyroid hormone receptor like family
topic nuclear receptor
thyroid hormone receptor-like family
ligand-binding domain
sequence conservation
phylogeny
relative entropy
url https://www.frontiersin.org/articles/10.3389/fendo.2022.981090/full
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