Recently, Professor Feng Shiqing and Professor Sun Jinpeng’s team and their collaborators published a research paper titled “Development of an allosteric adhesion GPCR nanobody with therapeutic potential” in Nature Chemical Biology. Adhesion G-protein-coupled receptors (aGPCRs), with large N termini, are ideal for allosteric modulator development. The study developed an allosteric nanobody of an aGPCR, ADGRG2, and gained insights into its functions in reversing disease-associated dysfunctions. It may serve as a template for developing allosteric modulators of other aGPCRs for biological and therapeutic purposes.

This study employed yeast display, cryo-EM structure determination, molecular dynamics simulation, BRET-based ligand binding assay, and detailed pharmacological analysis to identify an allosteric nanobody (Nb23-bi) of ADGRG2. Nb23-bi promoted dehydroepiandrosterone (DHEA)-induced ADGRG2 activation. An animal study showed that Nb23-bi promoted the response of DHEA in alleviating testicular inflammation. Nb23-bi was also able to reverse defects in disease-associated mutants both in vitro and in vivo, providing direct evidence for the longstanding hypothesis that an allosteric modulator of a GPCR might be an effective treatment for patients who express mutant GPCRs. The cryo-EM structures indicated that compared to the position of the endogenous agonist DHEA in the DHEA–ADGRG2–Gs complex, the position of DHEA in the Nb23-bi–DHEA–ADGRG2–Gs complex enabled the formation of more extensive interactions and deeper insertion. The interface between the nanobody Nb23-bi and ADGRG2 was the A domain of ADGRG2-NTF, and the epitope of ADGRG2 for nanobody recognition was also revealed.