Structural Insights Into Thyroid Hormone Receptors

[helvella]

This paper is not very helpful to us in terms of advancing treatment. But it might be of interest and help in understanding what goes on.

It is all too easy to read, then repeat terms like "receptor" and yet have next to no visualisation of what they are!

Or you can scroll through, view the pictures, and go "Wow!"

Being a review paper it does paint a more complete picture than the highly specific research papers. But the language does make some of it difficult to properly appreciate.

Structural Insights Into Thyroid Hormone Receptors

Endocrinology, Volume 166, Issue 1, January 2025, bqae154, doi.org/10.1210/endocr/bqae154

Abstract

Thyroid hormone receptors (TRs) are essential components of the endocrine system, mediating the cellular effects of thyroid hormones. The 2 TR genes, THRA and THRB, encode 4 isoforms, with TRα1 and TRβ1 being the most prevalent. TRs are ligand-dependent transcription factors and members of the nuclear receptor superfamily, indispensable for human growth, development, and metabolism. Dysfunctional TR signaling can lead to conditions such as resistance to thyroid hormone (RTH) syndrome, thyroid cancer, and metabolic disorders. Structurally, TRs comprise several domains: a variable N-terminal domain, a conserved DNA-binding domain, and a ligand-binding domain that mediates interaction with hormones and transcriptional coregulators. TRs predominantly function as heterodimers with the retinoid X receptor (RXR), binding to thyroid hormone response elements in target genes to regulate their transcription. This review examines the structural studies on TRs, primarily performed through x-ray crystallography, that have provided detailed insights into TR functions, including DNA recognition, ligand binding, and coregulator interactions. We also discuss how these findings have deepened our understanding of TR mechanisms and contributed to the interpretation of pathogenic mutations.

Keywords: thyroid hormone receptor, atomic structure, DNA recognition, ligand binding, coregulator interaction, pathological mutation

Open access:

academic.oup.com/endo/artic...

[jimh111]

A bit of light bedtime reading! An important point to note is the pituitary and hypothalamus have a different receptor type (TRB2) and can use homodimer binding. i.e. they are different to peripheral tissues in the way they bind thyroid hormone. Thus, you can have normal pituitary function with peripheral hypothyroidism. Hypothyroidism with normal TFTs. This happens with endocrine disrupting chemicals because the testing only looks for abnormal TFTs.

[arTistapple in reply to jimh111]

How does peripheral hypothyroidism look compared to say Hashimotos? Just no inflammatory markers?

[jimh111 in reply to arTistapple]

It can be somewhat different in emphasis because the TRB1 receptor tends to be most affected. In my case there was weight gain, brain fog, an inability to concentrate and IBS. My heart rate was only slightly low, almost normal, cholesterol elevated and I had a tendency to ADHD. So, the balance of symptoms is a little different.

[arTistapple in reply to jimh111]

How on Earth did you ever find out? I guess you had to do most of the work yourself as medics seem clueless to even the most obvious cases.

[jimh111 in reply to arTistapple]

Took twenty years of research, going to British Library, losing focus after fifteen minutes, going for walk / coffee, repeat. And the wonderful Dr Gordon Skinner.

[arTistapple in reply to jimh111]

I want to say above and beyond but really it’s been entirely your own endeavours into completely unknown territory. “Above and beyond” doesn’t cover it.

[BB001]

I used to think I was intelligent, then along came thyroid problems. Now I realise how little I knew.

[helvella Administrator in reply to BB001]

Wholly endorsed!