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

Majumdar, Ritankar; Railkar, Reema; Dighe, Rajan R.

doi:10.1074/jbc.m112.355032

Cited by 6 publications

(5 citation statements)

References 53 publications

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“…Circular dichroism (CD) spectra of glc-derived PAS and gal-derived PAS samples using experiment (A) in comparison to calculated CD analysis of 100 ps MD simulation of glc- and gal-PAS 10-mer structures from DichroCal. − Both spectra depict features indicative of helical conformations in both glc- and gal-PAS structures.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we computed CD spectra using glc- and gal-PAS polymer conformations derived from 100 ps of MD simulations with the Dichro-Cal − software program to determine whether the newly developed AA models reliably represented the glc- and gal-PAS systems (Figure B). In agreement with our experimental data, the calculated spectra showed strong CD signals with a positive peak around 198 nm (compared to the 191 nm in experiment) and a negative peak at 220 nm (compared to the 219 nm in experiment).…”

Section: Resultsmentioning

confidence: 99%

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Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides

Chin¹,

Lü

Dane³

et al. 2016

J. Am. Chem. Soc.

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Poly-amido-saccharides (PAS) are carbohydrate-based, enantiopure synthetic polymers in which sugar repeat units are joined by amide linkages. This unique and relatively rigid pyranose backbone contributes to their defined helical secondary structure and remarkable chemical properties. Glucose- (glc-) and galactose- (gal-) PAS 10-mer structures are synthesized and investigated with molecular dynamics (MD) simulations and experimental measurements. Quantum mechanical DFT energy minimization calculations, as well as experimental observables including circular dichroism, (1)H,(13)C-HSQC, and (1)H,(1)H-NOESY 2D-NMR studies, validated the all-atom simulation models produced using a modified CHARMM force field. Water radial distribution functions show distinct differences in the glc- and gal-PAS systems that correlate well with observed differences in solubility between gal-PASs and glc-PASs. The computational analysis and MD simulations are in good agreement with experimental results, validating the proposed models as reliable representations of novel glc- and gal-PASs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides

Chin¹,

Lü

Dane³

et al. 2016

J. Am. Chem. Soc.

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“…Monoclonal antibodies directed at TSHR have been studied as antagonists of TSHR activation by TSHRbinding agonists [17][18][19]. Blocking antibodies inhibit activation of TSHR by blocking the binding of GO-Igs to the extracellular domain of TSHR.…”

Section: Tshr-targeted Treatmentsmentioning

confidence: 99%

Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

Neumann¹,

Krieger²,

Gershengorn³

2020

Eur Thyroid J

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Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.

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“…Based on this structure, it was suggested that FSH binds to FSHR like "hands clasped" on the concave surface of the FSHR (9). However, this model did not include the hinge region, which is considered to play critical roles in receptor activation based on various biochemical studies (10)(11)(12). More recent studies strongly suggest unliganded ECD acts as a tethered inverse agonist imposing an inhibitory effect through the hinge region, which is converted to a stimulatory response upon ligand binding (13).…”

mentioning

confidence: 99%

“…Studies by site-directed mutagenesis, chimeric receptors, and naturally occurring mutations have demonstrated the critical role of extracellular loops and intracellular loops in FSHR function (6,12,17,18). They play key roles in ligand binding, cell surface receptor trafficking, signaling, and interaction with adaptor proteins (6).…”

mentioning

confidence: 99%

Allosteric Regulation of the Follicle-Stimulating Hormone Receptor

Sriraman

Palmer²

2018

Endocrinology

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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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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

Cited by 6 publications

References 53 publications

Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides

Combined Molecular Dynamics Simulations and Experimental Studies of the Structure and Dynamics of Poly-Amido-Saccharides

Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

Allosteric Regulation of the Follicle-Stimulating Hormone Receptor

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