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

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

The researchers first solved four cryo-electron microscopy (cryo-EM) structures of LHCGR, i.e., two wild-type receptor structures in inactive and active states, and two constitutively active mutated receptor structures.

They found that the active structures are bound to CG and the stimulatory G-protein (Gs), and 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.

To clarify the activation mechanism of LHCGR, the researchers proposed a unique “push and pull” LHCGR activation model by solving the inactive structure of full-length LHCGR, also the first single G-protein-coupled receptor (GPCR) structure through cryo-EM.

Based on this model, they found that 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, and that CG interaction by the hinge loop serves to pull the CG-ECD complex upward.

These findings not only offer a molecular basis for glycoprotein hormone recognition and activation of glycoprotein hormone receptors, but also provide crucial information for the drug design of small molecule agonists to treat glycoprotein hormone related disorders.