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| Scientists reveal the activation mechanism of melanocortin receptor |
Recently, the research group of Xu Huaqiang, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Mingwei Wang’s group, used cryo-electron microscopy to analyze for the first time that melanocortin receptor 1 (MC1R) binds to the endogenous ligand α-melanocyte stimulating hormone ( α-MSH) and synthetic peptide ligand Afamelanotide (Afamelanotide) and the three-dimensional structure of SHU9119 and downstream Gs protein complexes, revealing the molecular mechanism of ligand recognition by calcium ion as well as receptor activation and G protein coupling The general mechanism of the association
.
Related research results were published in "Cell Research"
Melanocortin is an endogenous polypeptide hormone composed of adrenocorticotropic hormone (ACTH) and three melanocyte-stimulating hormones (α-MSH, β-MSH, and γ-MSH).
They act on the melanocyte The receptors (MC1R-MC5R) are involved in physiological activities such as the body's stress response, energy balance, immune regulation, and pigmentation
.
The secretion of melanocortin is regulated by hormones such as ghrelin, leptin and insulin.
At present, a variety of melanocortin peptide analogues have been developed as treatments for diseases such as skin diseases, obesity, anorexia and type 2 diabetes.
Potential drugs
.
However, due to the lack of understanding of the structure of melanocortin and its receptor complex, the specific mechanism of the interaction between melanocortin and the five melanocortin receptors is still unclear
In this study, the researchers analyzed the cryo-EM structure of MC1R coupled to Gs protein complex under different ligand stimulation (α-MSH, Afamelanotide, and SHU9119), with resolutions of 3.
0 angstroms, 2.
7 angstroms, and 3.
1 angstroms, respectively.
.
Combined with structural analysis and functional experiments, they found that MC1R forms a larger opening on the outside of the transmembrane region to accommodate the "U"-shaped polypeptide ligand and calcium ions.
In addition, in the three-dimensional reconstruction of the Afamelanotide-MC1R-Gs complex, the researchers classified a complex conformation without the density of the Nb35 antibody
.
By comparing the structure without Nb35 and the structure bound with Nb35, the researchers found that Gs has a relatively loose conformation without Nb35, the αN helix moves upward, and Gβ is closer to MC1R and interacts with the receptor Helix 8; The latter truncated or mutated the amino acid that interacts with Gβ greatly reduced the ability of the receptor to couple to G protein, indicating that the interaction between Helix 8 and Gβ played an important role in the receptor's recruitment of G protein
This study provides a structural model for understanding the molecular mechanism of ligand recognition in the melanocortin system, and also provides a new idea for the design of drugs targeting the melanocortin receptor
.
The cryo-electron microscopy data of this work was collected on the cryo-electron microscopy platform of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences
.
Ma Shanshan, a PhD student at the Shanghai Institute of Materia Medica, and Chen Yan, a graduate student at Fudan University, are the co-first authors of the paper
Chinese Academy of Sciences
Related paper information: https://doi.
https://doi.
org/10.
1038/s41422-021-00557-y
