7EPT

Structural basis for the tethered peptide activation of adhesion GPCRs

Summary for 7EPT

• Entry DOI: 10.2210/pdb7ept/pdb
• EMDB information: 31232
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, 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, ... (6 entities in total)
• Functional Keywords: adhesion gpcr, gpr133, structural protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 138316.35

Authors

Ping, Y.-Q.,Xiao, P.,Yang, F.,Zhao, R.-J.,Guo, S.-C.,Yan, X.,Wu, X.,Liebscher, I.,Xu, H.E.,Sun, J.-P. (deposition date: 2021-04-27, release date: 2022-05-11, Last modification date: 2024-11-20)

Primary citation

Ping, Y.Q.,Xiao, P.,Yang, F.,Zhao, R.J.,Guo, S.C.,Yan, X.,Wu, X.,Zhang, C.,Lu, Y.,Zhao, F.,Zhou, F.,Xi, Y.T.,Yin, W.,Liu, F.Z.,He, D.F.,Zhang, D.L.,Zhu, Z.L.,Jiang, Y.,Du, L.,Feng, S.Q.,Schoneberg, T.,Liebscher, I.,Xu, H.E.,Sun, J.P.
Structural basis for the tethered peptide activation of adhesion GPCRs.
Nature, 604:763-770, 2022

PubMed Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W and the constitution of a hydrogen-bond network formed by Q/Y and the P/VφφG motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G coupling.

PubMed: 35418678
DOI: 10.1038/s41586-022-04619-y

Experimental method

ELECTRON MICROSCOPY (3 Å)