8YKD
Cryo-EM structure of ADGRG2-Gs complex with NTF nanobody
Summary for 8YKD
| Entry DOI | 10.2210/pdb8ykd/pdb |
| EMDB information | 39365 |
| Descriptor | Guanine nucleotide-binding protein G(s) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein subunit gamma, ... (7 entities in total) |
| Functional Keywords | gpcr, membrane protein |
| Biological source | Spodoptera More |
| Total number of polymer chains | 6 |
| Total formula weight | 233151.75 |
| Authors | Huang, S.M.,Sheng-chao, G. (deposition date: 2024-03-04, release date: 2025-08-13, Last modification date: 2025-10-08) |
| Primary citation | Zheng, Y.,Jiang, D.,Lu, Y.,Zhang, C.,Huang, S.M.,Lin, H.,Zhang, D.,Guo, S.,Han, J.,Chen, J.,He, Y.,Zhang, M.,Gao, Y.,Guo, Y.,Wei, R.,Xia, M.,Qin, Y.,Liu, Z.,Yang, F.,Ge, S.,Yi, F.,Yu, X.,Lin, H.,Xiao, P.,Sun, J.P.,Feng, S. Development of an allosteric adhesion GPCR nanobody with therapeutic potential. Nat.Chem.Biol., 21:1519-1530, 2025 Cited by PubMed Abstract: Allosteric modulation of receptor responses to endogenous agonists has therapeutic value, maintaining ligand profiles, reducing side effects and restoring mutant responses. Adhesion G-protein-coupled receptors (aGPCRs), with large N termini, are ideal for allosteric modulator development. We designed a nanobody strategy targeting ADGRG2 N-terminal fragments and got a specific nanobody Nb23-bi, which promoted dehydroepiandrosterone (DHEA)-induced ADGRG2 activation and reversed mutant-induced dysfunctions. By combining structural characterization, crosslinking mass spectrometry, mutational analysis and molecular dynamics simulations, we clarified the allosteric mechanism of how the Nb23-bi modulates conformational changes in the DHEA-binding pocket. Animal studies showed that Nb23-bi promoted the response of DHEA in alleviating testicular inflammation and reversing mutant defects. In summary, we developed an allosteric nanobody of ADGRG2 and gained insights into its functions in reversing disease-associated dysfunctions. Our study may serve as a template for developing allosteric modulators of other aGPCRs for biological and therapeutic purposes. PubMed: 40374856DOI: 10.1038/s41589-025-01896-2 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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