Kisspeptin was discovered in 1996. Its physiological importance became apparent when scientists discovered that kisspeptin works by binding to and activating its receptor, KISS1R. The KISS1R signaling pathway is considered an important upstream regulator of the hypothalamic-pituitary-gonadal axis.
Studies have shown that continuous administration of kisspeptin can restore the pulsatile secretion of luteinizing hormone, suggesting that the upstream KISS1R may be a better target for the treatment of reproductive diseases. Administration of KP-10 has been shown to be effective in treating reproductive disorders in animal models, but this endogenous ligand is easily metabolically degraded. Therefore, the development of more effective and stable agonists targeting KISS1R is a current research focus. In order to overcome the degradation and rapid clearance of kisspeptin in the body, medicinal chemists have developed kisspeptin-10 analogs such as TAK-448. These compounds exhibit better biological activity and longer duration of action than kisspeptin.
This study discovered the critical role of KISS1R's peripheral loop in receptor activation. This finding was confirmed by molecular dynamics simulations and functional mutation studies. The study revealed the reason why TAK-448 is superior to KP-10 in activation efficiency, providing a basis for rational optimization of KP-10 analogues. Furthermore, the TM6 region of KISS1R exhibits a unique angular deviation on the medial side of the receptor compared with other Gq-coupled receptors. This is a striking feature in the coupling of KISS1R to Gq proteins. Further, the study proposed the importance of the receptor TM5-ICL3-TM6 region in downstream Gq coupling. KP-10 and TAK-448 adopt similar conformations in the ligand-binding pocket of KISS1R. Their binding modes reveal that specific residues have important effects on ligand recognition and receptor activation.
The above structural studies lay the foundation for exploring the molecular mechanism of KISS1R peptide ligand recognition, receptor activation and its coupling with Gq protein. These structural and functional research results provide insights into challenges in the fields of reproduction and cancer treatment.
