Structures of full-length glycoprotein hormone receptor signalling complexes

Duan, Jia; Xu, Peiyu; Cheng, Xi; Mao, Chunyou; Croll, Tristan I.; He, Xinheng; Shi, Jingjing; Luan, Xiaodong; Yin, Wanchao; You, Erli; Liu, Qiufeng; Zhang, Shuyang; Jiang, Hualiang; Zhang, Yan; Jiang, Yi; Xu, Hao

doi:10.1038/s41586-021-03924-2

Cited by 64 publications

(84 citation statements)

References 50 publications

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“…3). Both interactions are similar to previous structures of glycoprotein hormones bound to their cognate receptors 18,19 , supporting the importance of the common GPHɑ in hormone binding (Supplementary Fig. 3).…”

Section: Structure Of Tsh-activated Tshr Bound To Gssupporting

confidence: 88%

“…TSH binds to a concave surface of the TSHR ECD leucine rich repeat (LRR) similar to previous structures of follicle stimulating hormone (FSH) bound to FSHR and chorionic gonadotropin (CG) bound to LH/CGR [17][18][19] (Supplementary Fig. 3).…”

Section: Structure Of Tsh-activated Tshr Bound To Gssupporting

confidence: 74%

“…Based on structures of the LH/CGR, Duan et. al proposed that a clash between the CG-β chain and the membrane bilayer drives activation by "pushing" the LH/CGR ECD away from the membrane bilayer 19 . Simultaneously, an additional interaction between the hinge loop and the common GPH-α chain "pulls" the ECD to the up state.…”

Section: Membrane Bilayer Is Critical For Tshr Activationmentioning

confidence: 99%

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Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Faust

Singh

Zhang

et al. 2022

Preprint

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Thyroid hormones are vital to growth and metabolism. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves' disease. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright conformation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody selects a similar upright conformation of the extracellular domain. Conformational changes in the extracellular domain are transduced to the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane domain. Rotation of the TSHR ECD relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to G protein-coupled receptors with large extracellular domains.

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Section: Structure Of Tsh-activated Tshr Bound To Gssupporting

confidence: 88%

Section: Structure Of Tsh-activated Tshr Bound To Gssupporting

confidence: 74%

Section: Membrane Bilayer Is Critical For Tshr Activationmentioning

confidence: 99%

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Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Faust

Singh

Zhang

et al. 2022

Preprint

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“…Allosteric modulators are thought to bind to the TMD of the receptor. Very recently, a study unravelled the cryo-electron microscopy structure of full-length LHCGR, revealing a ‘push-and-pull’ mechanism for the LHCGR activation, i.e., the ECD is pushed by the bound hCG and pulled by the hinge loop next to TMD ( 55 ). When Org43553, an allosteric agonist was used, it bound to a pocket of the TMD and interacted with a highly conserved 10-residue fragment (P10), thereby stabilizing the active conformation ( 55 ).…”

Section: Main Factors Disrupting Reproductive Functionsmentioning

confidence: 99%

“…Very recently, a study unravelled the cryo-electron microscopy structure of full-length LHCGR, revealing a ‘push-and-pull’ mechanism for the LHCGR activation, i.e., the ECD is pushed by the bound hCG and pulled by the hinge loop next to TMD ( 55 ). When Org43553, an allosteric agonist was used, it bound to a pocket of the TMD and interacted with a highly conserved 10-residue fragment (P10), thereby stabilizing the active conformation ( 55 ). While, LUF5771, an allosteric LHCGR inhibitor, interacted directly with hydrophobic aminoacids in the minor pocket formed between transmembrane helices 1-2 and 7, which restricted the receptor to a more inactive conformation ( 56 ).…”

Section: Main Factors Disrupting Reproductive Functionsmentioning

confidence: 99%

Endocrine Disruption of the Follicle-Stimulating Hormone Receptor Signaling During the Human Antral Follicle Growth

et al. 2021

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An increasing number of pollutants with endocrine disrupting potential are accumulating in the environment, increasing the exposure risk for humans. Several of them are known or suspected to interfere with endocrine signals, impairing reproductive functions. Follicle-stimulating hormone (FSH) is a glycoprotein playing an essential role in supporting antral follicle maturation and may be a target of disrupting chemicals (EDs) likely impacting female fertility. EDs may interfere with FSH-mediated signals at different levels, since they may modulate the mRNA or protein levels of both the hormone and its receptor (FSHR), perturb the functioning of partner membrane molecules, modify intracellular signal transduction pathways and gene expression. In vitro studies and animal models provided results helpful to understand ED modes of action and suggest that they could effectively play a role as molecules interfering with the female reproductive system. However, most of these data are potentially subjected to experimental limitations and need to be confirmed by long-term observations in human.

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Smart Droplets Stabilized by Designer Surfactants: From Biomimicry to Active Motion to Materials Healing

Yang,

Snyder,

Sathyan

et al. 2023

Adv Funct Materials

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The science and technologies of emulsion droplets have been a long‐term focus of extensive research endeavors for their practical utility across a breadth of industries, including pharmaceutical products, oil recovery processes, and the food sciences. However, with advances in materials chemistry and characterization tools, new emerging areas are arising with a focus on “smart droplets”. The versatility of emulsion droplets across is based on their ability to partition and create isolated systems with properties defined by the liquid–liquid interface, while preparative routes allow manipulation of droplet size, stability, and encapsulated contents. As described in this article, significant efforts are being devoted to creating new types of droplets by “activating” this interface through the incorporation of reactive structures that trigger droplet response to applied or environmental stimuli (e.g., pH, temperature, salt, or external fields). Moreover, parallels between droplets and live cells inspire efforts to conceive systems that resemble biological motifs or that can produce cellular behaviors that imitate biology (e.g., swarming, communication, or motion). The authors highlight recent advances in smart droplets, with emphasis on organic, polymer, and/or particle surfactants that give rise to inter‐droplet communication (via aggregation, fusion, division, or mass transfer), droplet vehicles for controlled delivery, autonomous droplet motion, and tunable emulsion inversion. Especially emphasized is the macromolecular design to produce reactive and functional surfactants, which are crucial to responsive droplet behavior and their underlying mechanisms. More generally, the exquisite interplay between materials science and biology inspires the review of this research area that provides unique opportunities for insight and inspiration into the capabilities of new droplet designs.

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Structures of full-length glycoprotein hormone receptor signalling complexes

Cited by 64 publications

References 50 publications

Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

Endocrine Disruption of the Follicle-Stimulating Hormone Receptor Signaling During the Human Antral Follicle Growth

Smart Droplets Stabilized by Designer Surfactants: From Biomimicry to Active Motion to Materials Healing

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