Mechanism of Tethered Agonist Binding to an Adhesion G-Protein-Coupled Receptor.

ABSTRACT: Adhesion GPCRs (ADGRs) contain a GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the receptor N-terminus and undergoes autoproteolysis at a highly conserved GPCR proteolysis (GPS) site to generate the N-terminal fragment (NTF) and transmembrane C-terminal fragment (CTF). Dissociation of NTF reveals a peptide tethered agonist (TA) which is responsible for the activation of the ADGRs. The NTF-bound ADGRs contain the encrypted TA that assumes a β-strand configuration within the GAIN domain, which is markedly different from a U-shaped α-helical configuration of TA in the active cryo-EM structures of ADGRs. However, how the TA dramatically changes its configuration and binds to the ADGR CTF remains unknown. In this study, we have performed all-atom enhanced sampling simulations

SUBMITTER: Joshi K 

PROVIDER: S-EPMC12340805 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature