Development of an allosteric adhesion GPCR nanobody with therapeutic potential

Bassilana, F., Nash, M. & Ludwig, M. G. Adhesion G protein-coupled receptors: opportunities for drug discovery. Nat. Rev. Drug Discov. 18, 869–884 (2019).

Article  CAS  PubMed  Google Scholar 

Bondarev, A. D. et al. Opportunities and challenges for drug discovery in modulating adhesion G protein-coupled receptor (GPCR) functions. Expert Opin. Drug Discov. 15, 1291–1307 (2020).

Article  CAS  PubMed  Google Scholar 

Hamann, J. et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharm. Rev. 67, 338–367 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Purcell, R. H. & Hall, R. A. Adhesion G protein-coupled receptors as drug targets. Annu. Rev. Pharmacol. Toxicol. 58, 429–449 (2018).

Article  CAS  PubMed  Google Scholar 

Paavola, K. J. & Hall, R. A. Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. Mol. Pharmacol. 82, 777–783 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xiao, P. et al. Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature 604, 771–778 (2022).

Article  CAS  PubMed  Google Scholar 

Scholz, N. et al. Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation. Nature 615, 945–953 (2023).

Article  CAS  PubMed  Google Scholar 

Mitgau, J. et al. The N terminus of adhesion G protein-coupled receptor GPR126/ADGRG6 as allosteric force integrator. Front. Cell Dev. Biol. 10, 873278 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Liebscher, I., Schoneberg, T. & Thor, D. Stachel-mediated activation of adhesion G protein-coupled receptors: insights from cryo-EM studies. Signal Transduct. Target. Ther. 7, 227 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Kuffer, A. et al. The prion protein is an agonistic ligand of the G protein-coupled receptor ADGRG6. Nature 536, 464–468 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Diamantopoulou, E. et al. Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant. eLife 8, e44889 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ping, Y. Q. et al. Structural basis for the tethered peptide activation of adhesion GPCRs. Nature 604, 763–770 (2022).

Article  CAS  PubMed  Google Scholar 

Lin, H. et al. Structures of the ADGRG2–Gs complex in apo and ligand-bound forms. Nat. Chem. Biol. 18, 1196–1203 (2022).

Article  CAS  PubMed  Google Scholar 

An, W. et al. Progesterone activates GPR126 to promote breast cancer development via the Gi pathway. Proc. Natl Acad. Sci. USA 119, e2117004119 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sun, Y. et al. Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology. J. Biol. Chem. 296, 100174 (2021).

Article  CAS  PubMed  Google Scholar 

Mao, C. et al. Conformational transitions and activation of the adhesion receptor CD97. Mol. Cell 84, 570–583 (2024).

Article  CAS  PubMed  Google Scholar 

Ping, Y. Q. et al. Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex. Nature 589, 620–626 (2021).

Article  CAS  PubMed  Google Scholar 

Paavola, K. J., Sidik, H., Zuchero, J. B., Eckart, M. & Talbot, W. S. Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci. Signal. 7, ra76 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Petersen, S. C. et al. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron 85, 755–769 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu, D. et al. CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells. Science 375, eabi5965 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kenakin, T. & Christopoulos, A. Measurements of ligand bias and functional affinity. Nat. Rev. Drug Discov. 12, 483 (2013).

Article  CAS  PubMed  Google Scholar 

Wootten, D., Christopoulos, A. & Sexton, P. M. Emerging paradigms in GPCR allostery: implications for drug discovery. Nat. Rev. Drug Discov. 12, 630–644 (2013).

Article  CAS  PubMed  Google Scholar 

Peterson, S. M. et al. Discovery and design of G protein-coupled receptor targeting antibodies. Expert Opin. Drug Discov. 18, 417–428 (2023).

Article  CAS  PubMed  Google Scholar 

Zhang, D. L. et al. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. eLife 7, e33432 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Davies, B. et al. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol. Cell. Biol. 24, 8642–8648 (2004).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang, B. et al. Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. Andrology 5, 954–957 (2017).

Article  CAS  PubMed  Google Scholar 

Yuan, P. et al. Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles. Andrology 7, 329–340 (2019).

Article  CAS  PubMed  Google Scholar 

Rutkowski, K., Sowa, P., Rutkowska-Talipska, J., Kuryliszyn-Moskal, A. & Rutkowski, R. Dehydroepiandrosterone (DHEA): hypes and hopes. Drugs 74, 1195–1207 (2014).

Article  CAS  PubMed  Google Scholar 

Savineau, J. P., Marthan, R. & Dumas de la Roque, E. Role of DHEA in cardiovascular diseases. Biochem. Pharmacol. 85, 718–726 (2013).

Article  CAS  PubMed  Google Scholar 

Jankowski, C. M. et al. Sex-specific effects of dehydroepiandrosterone (DHEA) on bone mineral density and body composition: a pooled analysis of four clinical trials. Clin. Endocrinol. 90, 293–300 (2019).

Article  CAS  Google Scholar 

Alexaki, V. I. et al. DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA–Akt1/2–CREB–Jmjd3 pathway. Mol. Psychiatry 23, 1410–1420 (2018).

Article  CAS  PubMed 

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