7WUI

Tethered peptide activation mechanism of adhesion GPCRs ADGRG2 and ADGRG4

Summary for 7WUI

• Entry DOI: 10.2210/pdb7wui/pdb
• EMDB information: 32836
• Descriptor: mini-Gs, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, adgrg2, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 256739.17

Authors

Guo, S.C.,He, Q.T.,Xiao, P.,Sun, J.P.,Yu, X. (deposition date: 2022-02-08, release date: 2022-04-27, Last modification date: 2024-11-13)

Primary citation

Xiao, P.,Guo, S.,Wen, X.,He, Q.T.,Lin, H.,Huang, S.M.,Gou, L.,Zhang, C.,Yang, Z.,Zhong, Y.N.,Yang, C.C.,Li, Y.,Gong, Z.,Tao, X.N.,Yang, Z.S.,Lu, Y.,Li, S.L.,He, J.Y.,Wang, C.,Zhang, L.,Kong, L.,Sun, J.P.,Yu, X.
Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.
Nature, 604:771-778, 2022

PubMed Abstract: Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and β subunits. A tethered agonism mediated by the 'Stachel sequence' of the β subunit has been proposed to have central roles in aGPCR activation. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the G heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-β-G complex and the ADGRG4-β-G complex (in which β indicates the β subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-G). The Stachel sequences of both ADGRG2-β and ADGRG4-β assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-β or ADGRG4-β extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-G complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-β structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs.

PubMed: 35418677
DOI: 10.1038/s41586-022-04590-8

Experimental method

ELECTRON MICROSCOPY (3.1 Å)