Structures of full-length glycoprotein hormone receptor signalling complexes

Area of Science:

• Structural Biology
• Endocrinology
• Molecular Pharmacology

Background:

• Luteinizing hormone (LH) and chorionic gonadotropin (CG) are critical glycoprotein hormones for reproduction.
• These hormones activate the luteinizing hormone-choriogonadotropin receptor (LHCGR), a G-protein-coupled receptor.
• LHCGR is a key target for therapeutic interventions in endocrine diseases.

Purpose of the Study:

• To elucidate the structural mechanisms of LHCGR activation by LH and CG.
• To understand the role of a conserved hinge region in receptor signaling.
• To provide a structural basis for the development of novel LHCGR-targeting drugs.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine four distinct structures of LHCGR.
• Structures captured wild-type LHCGR in inactive and active states, and a constitutively active mutant.
• Complex structures included bound CG, the Gs protein, and an allosteric agonist (Org43553).

Main Results:

• A 'push-and-pull' mechanism of receptor activation was identified, involving hormone binding and hinge loop dynamics.
• A conserved 10-residue fragment (P10) in the hinge loop acts as a tethered agonist, driving transmembrane domain conformational changes.
• The allosteric agonist Org43553 stabilizes the active receptor conformation by interacting with the P10 fragment.

Conclusions:

• These structures provide a unified model for understanding glycoprotein hormone receptor signaling.
• The findings offer critical insights into LHCGR activation and allosteric modulation.
• This work lays the foundation for structure-based drug discovery targeting endocrine disorders.