Journal
MEDCOMM
Volume 3, Issue 4, Pages -Publisher
WILEY
DOI: 10.1002/mco2.159
Keywords
cryo-EM; ECL2; GPCR; GPR17; protein structure
Categories
Funding
- Science, Technology, and Innovation Commission of Shenzhen Municipality [JCYJ20200109150019113]
- Shenzhen Key Laboratory [ZDSYS20190902093417963]
- Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation [HZQB-KCZYB-2020056]
- Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong
Ask authors/readers for more resources
The study elucidated the activation mechanism of GPR17-Gi complex, revealing the self-activation mechanism of GPR17 and the interaction of Gi with key residues in GPR17.
GPR17 is a class A orphan G protein-coupled receptor (GPCR) expressed in neurons and oligodendrocyte progenitors of the central nervous system (CNS). The signalling of GPR17 occurs through the heterotrimeric Gi, but its activation mechanism is unclear. Here, we employed cryo-electron microscopy (cryo-EM) technology to elucidate the structure of activated GPR17-Gi complex. The 3.02 angstrom resolution structure, together with mutagenesis studies, revealed that the extracellular loop2 of GPR17 occupied the orthosteric binding pocket to promote its self-activation. The active GPR17 carried several typical microswitches like other class A GPCRs. Moreover, the Gi interacted with the key residues of transmembrane helix 3 (TM3), the amphipathic helix 8 (Helix8), and intracellular loops 3 (ICL3) in GPR17 to engage in the receptor core. In summary, our results highlight the activation mechanism of GPR17 from the structural basis. Elucidating the structural and activation mechanism of GPR17 may facilitate the pharmacological intervention for acute/chronic CNS injury.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available