Mechanistic Understanding of the Palmitoylation of G_o Protein in the Allosteric Regulation of Adhesion Receptor GPR97

• Main Authors: Hao Zhang (Author), Guojun Chu (Author), Gaoming Wang (Author), Min Yao (Author), Shaoyong Lu (Author), Ting Chen (Author)
• Format: Book
• Published: MDPI AG, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Adhesion G-protein-coupled receptors (aGPCRs)-a major family of GPCRs-play critical roles in the regulation of tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that the palmitoylation of the C-terminal G_o protein is essential for G_o's efficient engagement with the active GPR97, the detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97−G_o complex in the presence or absence of G_o palmitoylation. The conformational landscapes analyzed by Markov state models revealed that the overall conformation of GPR97 is preferred to be fully active when interacting with palmitoylated G_o protein. Structural and energetic analyses indicated that the palmitoylation of G_o can allosterically stabilize the critical residues in the ligand-binding pocket of GPR97 and increase the affinity of the ligand for GPR97. Furthermore, the community network analysis suggests that the palmitoylation of G_o not only allosterically strengthens the internal interactions between G_αo and G_βγ, but also enhances the coupling between G_o and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the G_o protein, and offers guidance for future drug design of aGPCRs.

Item Description

10.3390/pharmaceutics14091856
1999-4923