Researchers Reveal Mechanism of Actions of Glycoprotein Hormones

Luteinizing hormone (LH) and chorionic gonadotropin (CG) are two related secreted hormones that bind to the same receptor LHCGR and play critical roles in sex development and human reproduction. LH and CG, members of glycoprotein hormone family, both are significant for therapeutic drugs treating reproductive and sex development disorders.

In a study published in Nature on September 22 of 2021, a joint team of researchers led by H. Eric XU, JIANG Yi from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and ZHANG Yan from Zhejiang University School of Medicine, revealed the mechanism of molecular recognition of CG and activation mechanism of LHCGR.

The researchers solved four cryo-EM structures of LHCGR, two wild-type receptor structures in inactive and active states, and two constitutively active mutated receptor structures. The active structures are bound to CG and the stimulatory G-protein (Gs).

They discovered that the extracellular domain (ECD) contains 11 irregular leucine-rich repeats (LRRs) that form a slightly curved tube, where CG binds to the concave inner surface in a handclasp fashion.

By solving the inactive structure of full length LHCGR, also the first single GPCR structure by cryo-EM, the researchers proposed a unique “push and pull” LHCGR activation model. The binding of CG to the inactive LHCGR would cause a clash of distal region of CG with the membrane layer, which may push the upward rotation of the CG-ECD complex. CG interaction by the hinge loop serves to pull the CG-ECD complex upward.

These findings provide crucial information for drug design of small molecule agonists to treat glycoprotein hormone related disorders and offer a molecular basis for glycoprotein hormone recognition and activation of glycoprotein hormone receptors.



Basis for hormone-induced receptor activation (image by DUAN Jia from H. Eric XU's Lab)





Keywords: glycoprotein hormones;GPCR;reproduction diseases 

DIAO Wentong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences