Autoantibody mimicry of hormone action at the thyrotropin receptor

Faust, Bryan; Billesboelle, Christian; Suomivuori, Carl‐Mikael; Singh, Isha; Zhang, Kaihua; Hoppe, Nicholas; Pinto-Duarte, António; Diedrich, Jolene K.; Muftuoglu, Yagmur; Szkudlinski, Mariusz W.; Saghatelian, Alan; Dror, Ron O.; Cheng, Yifan; Manglik, Aashish

doi:10.1038/s41586-022-05159-1

Cited by 24 publications

(27 citation statements)

References 81 publications

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“…2f; Supplementary Table 2), which further indicated that the extended hinge loop play a role to pull the FSH-FSHR_ECD to rotate away from the membrane layer into the active upright configuration (Fig. 2e), in a similar manner to CG binding with LHCGR and TSH binding with TSHR [17][18][19] .…”

Section: Mechanism Of Fsh-induced Fshr Activationmentioning

confidence: 79%

“…The superposition of the FSHR ECD structures reveals that the distal region of FSHβ would clash with the membrane layer (Fig. 2e), suggesting a collision push of FSH to rotate the FSHR ECD away from the membrane layer into the upright ECD position in the active FSHR structure, which is similar to CG binding with LHCGR 19 , and TSH binding with TSHR 17,18 . On the other side, the extended hinge loop from FSHR hinge region formed direct interactions with FSH (Supplementary Fig.…”

Section: Mechanism Of Fsh-induced Fshr Activationmentioning

confidence: 97%

“…There are three members of glycoprotein hormone receptors, FSHR, LHCGR and TSHR, which are activated to mainly couple the Gs protein and lead to up-regulation of the secondary message cAMP in cells 16 . Most recently, the cryo-electron microscopy (cyro-EM) structures of CG-LHCGR-Gs and TSH-TSHR-Gs complexes have also been determined [17][18][19] , further providing insights into hormone specificity and hormone-induced receptor activation. The structures of CG-LHCGR-Gs and TSH-TSHR-Gs complexes suggested that there might be a conserved activation mechanism among glycoprotein hormone receptors.…”

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confidence: 99%

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

Duan

Zhang

et al. 2023

Nat Commun

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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.

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Section: Mechanism Of Fsh-induced Fshr Activationmentioning

confidence: 79%

Section: Mechanism Of Fsh-induced Fshr Activationmentioning

confidence: 97%

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confidence: 99%

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

Duan

Zhang

et al. 2023

Nat Commun

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“…The structure of Gs-bound ADRB2 complexes has been resolved with the Nb35 as a structural chaperone ( 27 ). Because it recognizes the interface between Gαs Ras domain and Gβγ and prevents GTP dissociation when the trimer is bound to agonist-occupied receptor, Nb35 has helped solving the high resolution 3D structures of other active, Gs-coupled GPCRs, such as the thyrotropin receptor (TSHR) ( 72 , 73 ), the lutropin-choriogonadotropic hormone receptor (LHCGR) ( 74 ) or the adenosine receptor A2a (ADORA2A) ( 75 ) among others, in active, transducer-bound conformation. In contrast to the paradigm establishing that β-arrestins binding precludes Gα binding on the receptor in order to desensitize it, it has been demonstrated by single-particle electron microscopy that Gαs and β-arrestin 1 can bind simultaneously the GPCRs that strongly interact with β-arrestins, such as the vasopressin V2 receptor (AVPR2) ( 76 ).…”

Section: Intra-vhhs To Mimic Transducer Activitymentioning

confidence: 99%

Intracellular VHHs to monitor and modulate GPCR signaling

et al. 2022

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Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010’s. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or β-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery.

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“…Abnormalities in TSHR can lead to autoimmune diseases such as hypothyroidism and hyperthyroidism. Recent studies have elucidated the structures of the activated and inactivated states of TSHR with different types of antibodies, which provides a structural basis for subsequent antibody drug and small molecule drug discovery ( Duan et al, 2022 ; Faust et al, 2022 ).…”

Section: Roles Of Class a G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Guo²,

Fu³

et al. 2022

Front. Mol. Neurosci.

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The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient’s hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

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Autoantibody mimicry of hormone action at the thyrotropin receptor

Cited by 24 publications

References 81 publications

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

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

Intracellular VHHs to monitor and modulate GPCR signaling

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

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