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2024

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08

New discovery of kissin receptor, Chinese University of Hong Kong Du Yang and other teams reveal new ways to treat reproductive diseases

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Kisspeptin receptor (KISS1R) belongs to the class A peptide-gpcr family, plays a key role in the regulation of reproductive physiology after Kisspeptin stimulation, and is considered to be an attractive drug target for the treatment of reproductive diseases.

On August 16, 2024, Du Yang and Chen Geng of the Chinese University of Hong Kong jointly communicated with Chen Jing of Jining Medical CollegeScience Advances Published online entitled“Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor” of research papers.This study demonstrates that KISS1R can couple to the Gi / o pathway in addition to the known Gq / 11 pathway.

The authors further analyzed the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes binding to the synthetic agonist TAK448 and the structure of KISS1R-Gq complexes binding to the endogenous agonist KP54.These high-resolution structures provide a clear insight into the mechanism by which KISS1R is recognized by its ligand, helping to design high-affinity targeted drugs to improve therapeutic efficacy. In addition, structural and functional analysis showed that the conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) and the "wavy hook" of the Gα subunit may be the specific reason for the G protein-coupled KISS1R signal.

peptide hormoneIt is an important signaling molecule in the central and peripheral nervous system. At least 150 natural neuropeptides have been identified, most of which signal through the G protein-coupled receptor (gpcr).In humans, by KISS1gene codingPeptide kisspeptin (KPs) play an important role in the regulation of reproductive physiology after recognition by their receptors (KISS1R).Initially, the product of the KISS1 gene is an unstable and inactive 145 amino acid pre-polypeptide, which further requires proteolytic cleavage into a shorter active peptide fragment, the suffix of which refers to itsamino acid length[e. g. kisspeptin-10 (KP10),KP13, KP14 and KP54].In recent clinical trials, KP analogs with satisfactory affinity for KP receptors and water solubility, such as TAK448, have significant potential in the treatment of female reproductive disorders.The therapeutic potential. In addition to its established role in reproduction, KP-KISS1R signaling systems have recently been shown to be involved in the regulation of body weight, feeding, metabolism, energy balance, nonalcoholic fatty liver disease, and cancer immune surveillance. .

The molecular basis of KP receptor activation by KP has been extensively studied.For example, all active KP peptides typically share the same C- terminal region, which contains the Arg-Phe-NH2 sequence characteristic of the RF amide peptide family, which is responsible for binding to and activating KISS1R. In terms of the KP receptor,molecular dockingand mutagenesis analyses have identified several peptide-binding residues in the receptor, revealing possible mechanisms underlying KP recognition and KISS1R activation.However, due to the lack of clear structural information, these mechanisms may be imprecise, which hinders the understanding of signal activation mechanisms and drug design against KP receptors.

Some GPCRs may mainly bind to specific subtypes of G proteins to induce intracellular signal transduction, while some receptors may bind to multiple G protein subtypes in response to extracellular stimuli, such as cholecystokinin a receptor (CCKAR), somatostatin receptor 2 (SSTR2) and angiotensin II type 1 receptor (AT1R) of class a gpcr, and lactopotrophin 3 (ADGRL3) and GPR110 of class B gpcr . The mechanism of G-protein coupling selectivity remains one of the major problems in GPCR biology and has been shown to be very complex. In addition to coupling primarily to Gq/11 proteins, our studies also showed that KISS1R confounded signals through the Gi/o pathway (Figure 1A). It is increasingly recognized that specific G-protein signaling pathways have therapeutic relevance, while other signaling pathways are often associated with adverse effects. Therefore, elucidation of the underlying mechanisms driving the preferential interaction of G protein subtypes with KISS1R is of paramount importance.
In this study, the authors report the cryo-electron microscopy (cryo-EM) structures of KISS1R-Gq and KISS1R-Gi complexes bound to TAK448 and KISS1R-Gi complexes bound to KP54.These structures reveal the binding modes involved in receptor activation and identify the structural determinants of G-protein versatility and selectivity that lead to KISS1R.
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