Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor

Abstract

Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H6157.42 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.

Receptor cavity-based screening reveals potential allosteric modulators of gonadotropin receptors in carp (Cyprinus carpio)

“…To generate homology models for carp FSHR and LHR we used available crystal structures of human homologs (PDB ID: 7FIH & 8I2H, for cLHR and cFSHR, respectively) 7 29 , as the carp homologs displayed high similarity and features characteristic of human GTHRs. These glycoprotein receptors belong to the class-A rhodopsin-like family of GPCRs 30 , whose structure is generally divided into three parts (Fig.…”

“…Further, the P519T mutation on hFSHR ECL2 ultimately impaired adenylate cyclase stimulation in vitro 34, 35 . P519 hFSHR is highly conserved in hFSHR(P516 hLHCGR ), cFSHR(P498 cFSHR ) and cLHR(P533 cLHR ), and its mutation was reported to disrupt receptor trafficking to the cell surface and subsequently abolished FSH binding and cAMP production 29 . Therefore, the interaction of the ligand with this residue might explain its agonistic effect on cLHR and cFSHR.…”

A single‐domain intrabody targeting the follicle‐stimulating hormone receptor impacts FSH‐induced G protein‐dependent signalling

“…A movement of the N-term portion of TM6 helix, suggesting the major importance of ICL3 in FSHR activation [16]. Therefore, by targeting ICL3, iPRC1 might affect FSHR helix conformational transitions, hence activation.…”

A single domain intrabody targeting the follicle-stimulating hormone receptor (FSHR) impacts FSH-induced G protein-dependent signalling

“…Furthermore, we show that the epitope of iPRC1 overlaps amino acids N 558 to D 567 of FSHR ICL3. Yet, according to the recently described structure of the active Gαs-coupled FSHR stabilized with compound 716340, where the ICL3 structure is resolved, amino acid S 566 engages an interaction with Y 358 of the Gαs protein (16) (PDB 8I2G). This interaction would be disrupted by iPRC1, giving a possible explanation for partial activation of the Gαs protein.…”

“…The FSHR, together with the luteinizing hormone/choriogonadotropin (LHCGR) and thyroid stimulating hormone receptors (TSHR), constitute the subfamily of glycoprotein hormone receptors. Unlike other class A GPCRs, these three receptors are characterized by a large horseshoe-shaped extra-cellular domain, comprising the hormone binding domain (16). The FSH-stimulated FSHR primarily signals through Gs, the Gαs subunit leading to the production of the cAMP second messenger, thus activating protein kinase A (PKA).…”