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 .
Hence, it is called the hypothalamic - pituitary - thyroid HTP endocrine axis .
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
In view of the shortcomings of rapid metabolism and degradation of TRH in the body, short action time, and large negative endocrine effects, Japan's Tanabe Mitsubishi Corporation has developed the world's first approved oral thyrotropin-releasing hormone, Taltirelin ( Taltirelin, TAL).
, is a structural modification drug of
TRH ) .
TAL is mainly used to improve ataxia in patients with spinocerebellar degeneration, antagonize reserpine-induced hypothermia, and antagonize pentobarbital-induced sleep,
The excitatory effect of TAL on the CNS is 10 to 100 times stronger than that of TRH , and it is more stable than TRH in vivo and the duration of action is about 8 times longer than that of TRH .
TAL vs TRH
The affinity of the receptor is about 1/11 of that of TRH , and the endocrine effect of TAL is weaker than that of TRH
The research on the differential activation mechanism of TRH and TAL on the TRHR receptor will be of great significance for the engineering and optimization of TRHR -targeting peptide drugs .
Thyrotropin-releasing hormone receptor (TRHR) is an important neuropeptide receptor in the hypothalamic - pituitary - thyroid endocrine axis of HPT .
TRH activates TRHR to initiate cellular stress effects through the Gq/11 signaling pathway .
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 .
Similar to other class A GPCRs , agonist binding to TRHR promotes the interaction of TRHR with the G protein complex and initiates the downstream signaling system in the cell .
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 .
Structural alignment showed that the interaction distance between the six-membered heterocycle of TAL and N289 6.
58 was farther than that of pyroGlu of TRH , and the orientation difference between the second residue L-His of TAL and TRH in the ligand-binding pocket of TRHR resulted in The interaction between TAL and TRHR is weaker than that between TRH and TRHR , which means that TRH is more suitable for binding with TRHR , which may be the structural basis for the weaker TRHR affinity of TAL than TRH .
At the same time, binding TRHR in TRH or TAL
Afterwards, multiple amino acid side chains ( W279, Y282, Y310 ) in the Toggle switch and NPxxY regions were deflected to different degrees, making TRHR-Gq/TAL behave as TM5 that moved more outward than TRHR-Gq/TRH , TM6 , will lead to a tighter binding of TRHR to Gq under the action of TAL , which may be the structural basis for the stronger ability of TAL to activate TRHR signaling than TRH .
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
Professor Tian Changlin and Associate Professor Shi Pan of our school, and Professor Liu Lei of Tsinghua University are the co-corresponding authors
The research work was supported by the National Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences' Strategic Pilot B , and the Chinese Academy of Sciences' institutionalized research relying on major national science and technology infrastructure
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