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Recently, researcher Xu Huaqiang, researcher Jiang Yi, and researcher Zhang Yan of Zhejiang University, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, jointly published research papers in the top academic journal "Nature", revealing the structural basis and molecular mechanism of the interaction between glycoprotein hormones and receptors
.
Glycoprotein hormones, including gonadotropin, thyroid stimulating hormone, etc.
, are key drugs used in assisted reproduction and treatment of thyroid diseases
.
However, in the past, it was not clear how glycoprotein hormones activate receptors in human cells, thus limiting people's selectivity when using such hormones, and also restricting drug developers from targeting receptors to develop new drug molecules for alternative hormone therapy
Glycoprotein hormone receptors are a type of G protein-coupled receptors (GPCRs).
Due to the large extracellular region and other structural characteristics, it is difficult to recombine and express in vitro, and the full-length conformation is highly unstable
.
In this research, scientists have overcome technical difficulties and made breakthroughs by screening continuously activated mutations and adding small molecule inhibitors
This research team used single-particle cryo-electron microscopy technology to analyze the inactive state and multiple types of full-length LHCGR for the receptor that LH and chorionic gonadotropin (CG) act together.
The structure of the active state
.
According to the research institute, this is also the first electron microscope structure of a full-length single GPCR
▲Schematic diagram of glycoprotein hormone receptor structure, cryo-EM structure of LHCGR receptor and CG and Gs protein complex (picture source: reference [2])
By comparing the LHCGR structure in the inactivated state and the activated state, the researchers revealed the unique "push-pull" activation model of the glycoprotein hormone receptor
.
Specifically, the extracellular domain of the receptor is pushed by the bound hormones and pulled by the hinge loop extending next to the transmembrane region
The researchers found that in LHCGR and another glycoprotein hormone receptor FSHR (Follicle Stimulating Hormone Receptor), there is a highly conserved 10 amino acid residue fragment (P10) at the C-terminus of the hinge region, which is very important for the activation of the receptor.
, Induce the conformational changes of the transmembrane region and the G protein coupling
.
▲Comparison of electron microscope structure and activated state structure of LHCGR in inactivated state and receptor activation model (picture source: reference [2])
The researchers also analyzed the molecular details of the small molecule compound Org43553 in phase 1 clinical trials that recognize LHCGR, revealing the binding pocket of the allosteric agonist Org43553
.
These results provide an important structural template for the clinical development of selective small molecule drugs targeting LHCGR and other glycoprotein hormone receptors
Note: The original text has been deleted
Reference materials:
[1] Duan, J.
[2] Nature | Shanghai Institute of Medicine Xu Huaqiang/Jiang Yi team cooperated to reveal the mechanism of glycoprotein hormone Retrieved Sep.
