
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.07.611823
preprint
1
Article
Mechanisms of peptide agonist dissociation and deactivation of adhesion G-protein-coupled receptors
Joshi Keya http://orcid.org/0009-0001-8139-478X

Miao Yinglong http://orcid.org/0000-0003-3714-1395

14 9 2024
2024.09.07.611823https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.09.07.611823
nihpp-2024.09.07.611823.pdf
ABSTRACT

Adhesion G protein–coupled receptors (ADGRs) belong to Class B2 of GPCRs and are involved in a wide array of important physiological processes. ADGRs contain a GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the receptor N-terminus and undergoes autoproteolysis during biosynthesis to generate two fragments: the N-terminal fragment (NTF) and C-terminal fragment (CTF). Dissociation of NTF reveals a tethered agonist to activate CTF of ADGRs for G protein signaling. Synthetic peptides that mimic the tethered agonist can also activate the ADGRs. However, mechanisms of peptide agonist dissociation and deactivation of ADGRs remain poorly understood. In this study, we have performed all-atom enhanced sampling simulations using a novel Protein-Protein Interaction-Gaussian accelerated Molecular Dynamics (PPI-GaMD) method on the ADGRG2-IP15 and ADGRG1-P7 complexes. The PPI-GaMD simulations captured dissociation of the IP15 and P7 peptide agonists from their target receptors. We were able to identify important low-energy conformations of ADGRG2 and ADGRG1 in the active, intermediate, and inactive states, as well as exploring different states of the peptide agonists IP15 and P7 during dissociation. Therefore, our PPI-GaMD simulations have revealed dynamic mechanisms of peptide agonist dissociation and deactivation of ADGRG1 and ADGRG2, which will facilitate rational design of peptide regulators of the two receptors and other ADGRs.
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pmc
