2022-04-19 Cell Research Tian Changlin's research group reveals the structural basis for the activation of thyrotropin-releasing receptor by endogenous peptides and oral peptide drugs in the HPT endocrine axis

<>

On March 29 , 2022 , the team of Professor Tian Changlin of our school, in cooperation with the team of Professor Liu Lei from the Department of Chemistry of Tsinghua University and the Key Laboratory of Organophosphorus Chemistry and Chemical Biology of the Ministry of Education , published a paper entitled " Structuralinsightsinto thyrotropin releasing hormone receptor activation by an endogenouspeptideagonist orits orally administered analog" research paper .

Thyrotropin Releasing Hormone ( TRH ) is a tripeptide hormone secreted by the hypothalamus, stimulates the anterior pituitary to release Thyroid Stimulating Hormone (TSH ) , TSH stimulates the thyroid to secrete thyroid hormone, and thyroid hormone significantly promotes the baby During the period of growth and development, it can promote the metabolism and synthesis of bone, skeletal muscle and liver, and increase the basal metabolic rate of adults .

TRH has been developed as an injectable tripeptide drug (prorelin) , used in endocrinology for the treatment of hypothalamic hypothyroidism and central hyperthyroidism; in psychiatry for the treatment of depression and schizophrenia; in neurology For the treatment of brain and spinal cord injury and coma, amyotrophic lateral sclerosis, spinocerebellar degeneration, senile dementia, epilepsy and other diseases

Figure 1.

By solving the three-dimensional structure of the TRHR/Gq complex in combination with the endogenous tripeptide agonist TRH (prorelin) or the oral peptide agonist TAL (tatirelin), combined with functional analysis, this study revealed that TRH (pyroGlu -His-Pro-NH2 ₎ interaction with TRHR , and TAL(1-methyl-(S)-4,5-dihydroorotyl)-His-Pro- _NH2 ) interaction with TRHR .

Figure 2 : TRHR/miniGq complex binds to the agonist TRH (prorelin) or TAL (tatirelin) electron microscope structure TAL has a lower affinity for TRHR than TRH , but the effect is stronger than TRH

Compared with the hydrophilic first residue pyro-Glu in TRH , the first residue of TAL is replaced by a nitrogen-containing heterocycle with highly hydrophobic properties, which is the main reason for the strong hydrophobicity and oral properties of TAL .

TRH or TAL , respectively, form specific interactions with amino acids surrounding the ligand-binding pocket of TRHR through multiple hydrogen -bonding interactions .

Figure 3 : The detailed differences in the interaction between TRH and TAL and TRHR , and the differences in the conformational changes in the transmembrane region caused by TRH or TAL binding to TRHR , may be the structural basis for the differences in intracellular Gq protein binding

The first authors of this research paper are postdoctoral fellow Yang Fan, master student Zhang Huanhuan, and doctoral student Meng Xianyu

Article link: https:// class="cjk" >