Structure-based Nuclear Receptors Modeling for Auditory and Otology Research

Thyroid hormone stimulates development in many systems, among which the auditory system is one of the most sensitive targets. Almost all actions of thyroid hormone are mediated by its nuclear receptors. The thyroid hormone receptor (THR) acts as a ligand-regulated transcription factor, suggesting a model whereby the thyroid hormone promotes hearing by regulation of gene expression in tissues of the auditory system. Creative Biolabs has focused on the development of computational pharmacology services for many years and has established excellent platforms for drug development. We provide a variety of nuclear receptors modeling services to meet the diverse needs of our customers.

THR in Auditory System

The major form of thyroid hormone in the circulation is L-thyroxine (T4), a tetraiodinated form that is derived from iodinated tyrosyl residues in thyroglobulin protein in the thyroid gland. L-triiodothyronine (T3) is the biologically active form of the hormone that binds to the THR with high affinity. Abnormalities of the thyroid gland have long been associated with hearing loss in human disease. For example, deafness is well-known in geographical regions in which endemic goiter exists. This developmental disorder of neurological and physical retardation results from a chronic deficiency of dietary iodine, an essential element required for the synthesis of thyroid hormone. Mutations in the thyroid hormone receptor β (THRβ) gene in the syndrome of resistance to thyroid hormone have also been associated with hearing loss.

The main isoforms of THRs, THRα1, THRβ1, and THRβ2, are predominantly responsible for mediating thyroid hormone action, which is critical for normal development, growth, and metabolism. The THR has the typical structure of a nuclear receptor with a central DNA binding domain and a C-terminal ligand (T3) binding domain. The THR binds to promoter or enhancer regions of target genes, usually as a homodimer or heterodimer with retinoid X receptor (RXR). The binding sites usually contain a consensus AGGTCA motif, often as a direct repeat with a four-base spacing.

For positive-response genes, T3 binding induces a conformational shift in the THR that displaces corepressors, and recruits coactivators and chromatin-modifying complexes, and activates gene transcription.
For negative-response genes, T3 binding to the THR suppresses transcription. Currently, little is known of the target genes of the THR in the auditory system.

Fig.1 Model of gene regulation by thyroid hormones.

Services

Currently, although certain compounds have been discovered as targeted therapy, it is restricted because some THRs ligands may trigger a mixture of favorable and deleterious actions, for instance, thyroid hormones lead to weight loss by increasing metabolism and improving lipid balance, however, it also causes heart failure, muscle wasting, and osteoporosis. Therefore, it is desirable to develop selective THRs agonists that would induce beneficial effects but do not have unfavorable effects. In addition, previous researches have suggested that THRβ specific agonists would have some desirable properties. We can provide a variety of structure-based nuclear receptors modeling approaches to meet customers’ specific requirements.

Creative Biolabs offers a broad variety of nuclear models for our worldwide clients. With years of experience in the field of computational pharmacology as well as excellent professional skills, our scientists are proud to help you identify the most appropriate nuclear receptor models for your research of interest. If you are interested in our services, please contact us for more details.

All listed services and products are For Research Use Only. Do Not use in any diagnostic or therapeutic applications.

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