scholarly journals The Antibodies against the Computationally Designed Mimic of the Glycoprotein Hormone Receptor Transmembrane Domain Provide Insights into Receptor Activation and Suppress the Constitutively Activated Receptor Mutants

2012 ◽  
Vol 287 (41) ◽  
pp. 34514-34532 ◽  
Author(s):  
Ritankar Majumdar ◽  
Reema Railkar ◽  
Rajan R. Dighe
Keyword(s):  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Glycoprotein Hormone ◽  
Glycoprotein Hormone Receptor

scholarly journals A conformational contribution of the luteinizing hormone–receptor ectodomain to receptor activation

2007 ◽  
Vol 38 (2) ◽  
pp. 259-275 ◽  
Author(s):  
Pascal Nurwakagari ◽  
Andreas Breit ◽  
Claudia Hess ◽  
Hagar Salman-Livny ◽  
David Ben-Menahem ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Inverse Agonist ◽  
Luteinizing Hormone Receptor ◽  
Receptor Activity ◽  
Activation Mechanism ◽  
Glycoprotein Hormone

Glycoprotein hormone receptors such as the lutropin/chorionic gonadotropin receptor (LHR) are characterized by a large N-terminal ectodomain (ECD), which is responsible for hormone–receptor interactions. For the closely related TSH receptor (TSHR), it has been proposed that the ECD also serves as a tethered inverse agonist. However, the exact role of the LHR–ECD for receptor activation remains elusive. Functional analysis of N-terminally truncated LHR mutants expressed in COS-7 cells revealed that the LHR–ECD does not act as an inverse agonist but facilitates active LHR conformations. This notion is supported by two observations: first, removal of the ECD tended to decrease basal LHR activity and secondly, mutationally induced constitutive receptor activity was diminished for most activating mutations in LHR lacking the ECD. In addition, swapping of the LHR–ECD for the ECD of the closely related TSHR was not sufficient to restore constitutive receptor activity induced by naturally occurring activating heptahelical LHR mutations. Thus, the ECD stabilizes an activation-competent conformation of the heptahelical region. While the full-length LHR fused to the cognate agonist, human chorionic gonadotropin (hCG), showed increased basal activity, fusion proteins between hCG and N-terminally truncated LHR did not yield constitutive receptor activity suggesting an important role of the ECD also for agonist-dependent LHR activity. Our experiments strengthen the concept of a major contribution of the LHR–ECD in the activation mechanism apart from hormone binding and provide evidence for a cooperative model with structural and functional interactions of the ECD and the transmembrane domain.

scholarly journals Actions of the Small Molecule Ligands SW106 and AH-3960 on the Type-1 Parathyroid Hormone Receptor

2015 ◽  
Vol 29 (2) ◽  
pp. 307-321 ◽  
Author(s):  
Percy H. Carter ◽  
Thomas Dean ◽  
Brijesh Bhayana ◽  
Ashok Khatri ◽  
Raj Rajur ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Small Molecule ◽  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Blood Calcium ◽  
Parathyroid Hormone Receptor ◽  
Peptide Analog ◽  
Amino Terminal ◽  
Small Molecule Ligands

Abstract The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a well-defined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1-delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1–11), as well as by the native PTH(1–9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1.

Structures of full-length glycoprotein hormone receptor signalling complexes

Nature ◽  
2021 ◽  
Author(s):  
Jia Duan ◽  
Peiyu Xu ◽  
Xi Cheng ◽  
Chunyou Mao ◽  
Tristan Croll ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Full Length ◽  
Glycoprotein Hormone ◽  
Receptor Signalling ◽  
Glycoprotein Hormone Receptor

scholarly journals A sea lamprey glycoprotein hormone receptor similar with gnathostome thyrotropin hormone receptor

2008 ◽  
Vol 41 (4) ◽  
pp. 219-228 ◽  
Author(s):  
Mihael Freamat ◽  
Stacia A Sower
Keyword(s):  
Hormone Receptor ◽  
Hormone Receptors ◽  
Functional Divergence ◽  
Sea Lamprey ◽  
Glycoprotein Hormone ◽  
Receptor System ◽  
Glycoprotein Hormone Receptors ◽  
Molecular Phylogenetic ◽  
Synthetic Ligand ◽  
Glycoprotein Hormone Receptor

The specificity of the vertebrate hypothalamic–pituitary–gonadal and hypothalamic–pituitary–thyroid axes is explained by the evolutionary refinement of the specificity of expression and selectivity of interaction between the glycoprotein hormones GpH (FSH, LH, and TSH) and their cognate receptors GpH-R (FSH-R, LH-R, and TSH-R). These two finely tuned signaling pathways evolved by gene duplication and functional divergence from an ancestral GpH/GpH-R pair. Comparative analysis of the protochordate and gnathostome endocrine systems suggests that this process took place prior or concomitantly with the emergence of the gnathostome lineage. Here, we report identification and characterization of a novel glycoprotein hormone receptor (lGpH-R II) in the Agnathan sea lamprey. This 781 residue protein was found ∼43% identical with mammalian TSH-R and FSH-R representative sequences, and similarly with these two classes of mammalian receptors it is assembled from ten exons. A synthetic ligand containing the lamprey glycoprotein hormone β-chain tethered upstream of a mammalian α-chain activated the lGpH-R II expressed in COS-7 cells but in a lesser extent than lGpH-R I. Molecular phylogenetic analysis of vertebrate GpH-R protein sequences suggests a closer relationship between lGpH-R II and gnathostome thyrotropin receptors. Overall, the presence and characteristics of the lamprey glycoprotein hormone receptors suggest existence of a primitive functionally overlapping glycoprotein hormone/glycoprotein hormone receptor system in this animal.

scholarly journals GRIS: Glycoprotein-Hormone Receptor Information System

2006 ◽  
Vol 20 (9) ◽  
pp. 2247-2255 ◽  
Author(s):  
Joost Van Durme ◽  
Florence Horn ◽  
Sabine Costagliola ◽  
Gert Vriend ◽  
Gilbert Vassart
Keyword(s):  
Information System ◽  
Hormone Receptor ◽  
Glycoprotein Hormone ◽  
Glycoprotein Hormone Receptor

scholarly journals Glycoprotein Hormone Receptor Knockdown Leads to Reduced Reproductive Success in Male Aedes aegypti

2019 ◽  
Vol 10 ◽  
Author(s):  
David A. Rocco ◽  
Ana S. G. Garcia ◽  
Elton L. Scudeler ◽  
Daniela C. dos Santos ◽  
Rafael H. Nóbrega ◽  
...  
Keyword(s):  
Reproductive Success ◽  
Aedes Aegypti ◽  
Hormone Receptor ◽  
Glycoprotein Hormone ◽  
Glycoprotein Hormone Receptor

1-Methyladenine: a starfish oocyte maturation-inducing substance

Zygote ◽  
1999 ◽  
Vol 8 (S1) ◽  
pp. S9-S11 ◽  
Author(s):  
Masatoshi Mita
Keyword(s):  
Oocyte Maturation ◽  
Hormone Receptor ◽  
Ovarian Follicle ◽  
Germinal Vesicle ◽  
Follicle Cells ◽  
Glycoprotein Hormone ◽  
Late Prophase ◽  
Immature Oocytes ◽  
Extracellular Region ◽  
Glycoprotein Hormone Receptor

1-Methyladenine (1-MeAde) in starfish was the first compound to be identified as an oocyte maturation-inducing substance (MIS) among invertebrates in 1969 by Kanatani and co-workers. In starfish, the ripe ovary contains a huge number of fully grown oocytes of almost equal size. Each oocyte possesses a large nucleus (germinal vesicle, GV), which is arrested in late prophase of the first maturation division. The oocyte is surrounded by a single follicle layer. Such immature oocytes are not fertilisable. Resumption of meiosis in immature oocytes can be induced by 1-MeAde, and the mature oocytes thus become fertilisable (Kanatani et al., 1969; Kanatani, 1985). 1-MeAde is produced by ovarian follicle cells upon stimulation with a gonad-stimulating substance (GSS) released from the radial nerves (Fig. 1).It has been demonstrated that GSS is a peptide hormone (Kanatani et al., 1971). The action of GSS on 1-MeAde production in follicle cells appears to be mediated by its receptor, G-proteins and adenylyl cyclase (Mita & Nagahama, 1991). These findings suggest that a G-protein coupled (seven transmembrane type) receptor is involved in GSS signal transduction, similarly to the pituitary-gonadal axis in vertebrates.Thus, using degenerate probes derived from consensus sequences of the mammalian glycoprotein hormone (GTH and TSH) receptors, cDNA was cloned from mRNA of ovaries of Asterina pectinifera. The cDNA showed striking structural homology with members of the glycoprotein hormone receptor family in the transmembrane region, and contained a very large extracellular region. Expression was observed in isolated ovarian follicle cells. Thus, it seems likely that the glycoprotein hormone receptor (GTHR) family gene is related to GSS receptor in ovarian follicle cells. The phylogenic relatedness of the starfish GTHR was also assessed in relation to other vertebrate GTHRs. The analysis showed that the starfish gene diverged before differentiation of the gonadotropin (LH and FSH) and TSH receptors in vertebrates.

scholarly journals Allosteric Regulation of the Follicle-Stimulating Hormone Receptor

Endocrinology ◽  
2018 ◽  
Vol 159 (7) ◽  
pp. 2704-2716 ◽  
Author(s):  
Selvaraj Nataraja ◽  
Venkataraman Sriraman ◽  
Stephen Palmer
Keyword(s):  
Small Molecule ◽  
Hormone Receptor ◽  
Follicle Stimulating Hormone ◽  
Receptor Activation ◽  
Luteinizing Hormone Receptor ◽  
Receptor Interaction ◽  
Surface Binding ◽  
Glycoprotein Hormone ◽  
Small Molecule Modulators ◽  
Stimulating Hormone

Abstract Follicle-stimulating hormone receptor (FSHR) belongs to the leucine-rich repeat family of the G protein–coupled receptor (LGR), which includes the glycoprotein hormone receptors luteinizing hormone receptor, thyrotropin receptor, and other LGRs 4, 5, 6, and 7. FSH is the key regulator of folliculogenesis in females and spermatogenesis in males. FSH elicits its physiological response through its cognate receptor on the cell surface. Binding of the hormone FSH to its receptor FSHR brings about conformational changes in the receptor that are transduced through the transmembrane domain to the intracellular region, where the downstream effector interaction takes place, leading to activation of the downstream signaling cascade. Identification of small molecules that could activate or antagonize FSHR provided interesting tools to study the signal transduction mechanism of the receptor. However, because of the nature of the ligand-receptor interaction of FSH-FSHR, which contains multiple sites in the extracellular binding domain, most of the small-molecule modulators of FSHR are unable to bind to the orthosteric site of the receptors. Rather they modulate receptor activation through allosteric sites in the transmembrane region. This review will discuss allosteric modulation of FSHR primarily through the discovery of small-molecule modulators, focusing on current data on the status of development and the utility of these as tools to better understand signaling mechanisms.

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